I remember this passage, from Iris Murdoch's "The Flight from the Enchanter", every day, and especially when I receive information that may cause me to modify my hypothesis.
Reading up on cholesterol with regard to Dr Yu's study that I discussed in my last post (a study of chronic hepatitis C cases, non-responders, showing increased progression of fibrosis and cirrhosis with higher cholesterol intakes), it becomes quite obvious that cholesterol should have a role in fibrosis and cirrhosis.
Apt tune; Rufus Wainright, Cigarettes and Chocolate Milk
You can cause fatty liver in an animal with a variety of strategies; a methionine-choline deficient diet, alcohol plus linoleic acid, a high fat diet (unless the fat is butter or coconut oil, or the animal is intermittently fasted); or fructose plus linoleic acid. The latter two are models of NAFLD (non-alcoholic fatty liver disease). NAFLD can progress to NASH, non-alcoholic steatohepatitis, an inflammatory disease which results in fibrosis and cirrhosis.
What is needed to turn NAFLD into NASH in rodents? Dietary cholesterol. 1% (which is a lot).
What happens if cholesterol is added to the alcohol-linoleic acid (or indeed fish oil) model of alcoholic liver disease?
In rats given intragastric ethanol and either corn or fish oil,
addition of cholesterol (1%) does not change the degree of
fatty infiltration but prevents hepatic necrosis and inflammation
and enhances hepatic fibrosis. Cholesterol in this model
decreases the enhanced low-density lipoprotein receptor
message, eliminates messages for TNF-a and COX-2, and
decreases plasma and liver levels of thromboxane B2, and
products of lipid peroxidation, whereas it increases transforming
growth factor-b message. The anti-inflammatory effects of
cholesterol are most likely related to a decreased uptake of
arachidonic acid caused by downregulation of the low density
lipoprotein receptor and its decreased conversion to
eicosanoids via decreased COX-2 activity. Enhanced fibrosis
may be mediated by increased transforming growth factor-b.
(TGF-beta being a signal that activates hepatic stellate cells).
What happens in a non-alcohol model?
Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro- and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress.
Dietary cholesterol appears to confer a second “hit” that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress.
What sorts of factors that set the stage for a NASH-like syndrome might be present in HCV patients?
(Note that HCV fibrosis differs from NASH in that it is spread more evenly through the liver, consistent perhaps with an intracellular causative agent).
The NAFLD diet above is described as "diabetogenic", and NAFLD is associated with diabetes, obesity, and metabolic syndrome. The animal diets that cause it and predispose to NASH require the same nutrients that, frankly, cause diabetes and NAFLD in humans. Seed oils, lard, and refined carbohydrates that are predominantly sugar (also fish oil, but only in doses that no-one ever ate). Round the clock feeding and overfeeding. Factor in HCV, which is diabetogenic in its own way and (Genotype 3) promotes steatosis (incidentally, Genotype 3 does the most to depress cholesterol completion, and would logically benefit most from dietary cholesterol were the NASH issue moot).
Another point that might be of major importance to humans is the n-6:n-3 ratio.
Introduction and aim: Essential dietary polyunsaturated fatty acids (PUFA) include omega-6 (n-6) linoleic acid (18:2) which is metabolized to arachidonic acid (AA) and omega-3 (n-3) linolenic acid (18:3) which is metabolized to eicosapentanoic acid (EPA). Imbalance in secondary eicosanoids and prostaglandin metabolites of n-6 and n-3 PUFA are implicated in disorders related to the metabolic syndrome. Skeletal muscle PUFA influences systemic insulin sensitivity (Borkman 1993) and diets rich in omega-3 fatty acids are associated with diminished histological injury in NASH (Musso 2003). Erythrocyte membrane lipids reflect dietary intake of essential fatty acid over preceding months. We measured erythrocyte n-6:n-3 ratio in a cohort of patients as part of a larger study of omega-3 fatty acid therapy of NASH.
Methods: 15 patients (10 female) underwent analysis of erythrocyte lipid composition using capillary gas chromatography (Metametrix, Duluth, GA) to determine the AA:EPA ratio. The mean age was 50 ± 13 years all with liver biopsy NAS score ≥ 5 and a range of non-cirrhotic fibrosis stages of stage 1 (n = 6), stage 2 (n = 5) and stage 3 (n = 4).
Results: The mean AA:EPA was 65 ± 34 reflecting a relative excess of n-6 PUFA overall. However, a broad range was noted from 15 to 144 AA:EPA. Dividing the group into quintiles of the reference range, 9 of the patients fell into the highest (5th) quintile (AA:EPA = 84 ± 30) compared to the remaining 6 patients (AA:EPA = 36 ± 16, p = 0.001). There was no statistically significant difference in the histological stage between these groups (fibrosis score = 2 ± 0.9 versus 1.7 ± 0.8) although the higher AA:EPA group was significantly older (55±12 versus 39±12, p=0.01).
Conclusion: There is heterogeneity of AA:EPA in non-cirrhotic NASH patients and an age-related increase in n-6 to n-3 PUFA evident in the AA:EPA ratio of erythrocyte lipids. Further work is needed to understand if this reflects dietary differences and how this might influence response to omega-3 fatty acid therapy.
There is a 2012 review of Omega-3 interventions in NAFLD/NASH here.
If I might digress for a moment, I came across 2 very interesting epidemiological papers about age-related macular degeneration (AMD). Both identified linoleic acid as a factor promoting the disease, and a protective effect of fish oil and fatty fish - but this protective effect was only seen in those subjects with the lowest intake of linoleic acid:
Higher intake of specific types of fat--including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid--rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low. Conversely, neither omega-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake.
Note that this first paper distinguished between vegetable and animal fats and only found a harmful association with vegetable fats. The second paper combined all fats:
Saturated, monounsaturated, polyunsaturated, and transunsaturated fats increased the likelihood of progression (RR, 2.09 and P trend =.08; RR, 2.21 and P trend =.04; RR, 2.28 and P trend =.04; RR, 2.39 and P trend =.008, respectively). Higher fish intake was associated with a lower risk of AMD progression among subjects with lower linoleic acid intake. Processed baked goods, which are higher in some of these fats, increased the rate of AMD progression approximately 2-fold, and nuts were protective.
Note that nuts were protective against a linoleic acid mediated disease. I hope the significance of that is not lost on you!
Well here we have someone eating a standard western diet, lots of refined starches, sugars and omega 6 oils.
They decide to throw in a bit of cholesterol, say a bacon burger and an egg McMuffin, and their NAFLD is more likely to turn to NASH.
What about people with chronic HCV infection?
Factors associated with the presence of nonalcoholic steatohepatitis in patients with chronic hepatitis C.
What the results summarized in this post do suggest is that pork consumption may not be a problem at all, unless you become obese from eating it. How do you get obese from eating pork? Eating it together with industrial foods that are addictive would probably help.
Even then, there may well may be a brief transition period in which it may be wise to limit cholesterol. Exactly how much, I haven't a clue.