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Writer's pictureDr. Thomas J. Lewis

"Cholesterol" is a U-Curve



Dr. Carter and I have several people in our program who have very LOW "cholesterol." As you know, if you listened to our talks on "cholesterol" that, when the medical industry says "cholesterol," they really mean LDL - or low density lipoprotein. The closest thing to LDL outside of the body is SOAP.


Soap carries fats (grease, oils) through water. Without soap, the fats are not soluble or miscible, and thus cannot be removed or moved by water alone. LDL and other lipoproteins (HDL as the other most common one), behave just like soap. They carry fat-soluble substances like: vitamin A, D, E, K, EPA, DHA, cholesterol, triglycerides and other fatty substances through your water-based blood stream. In other words, LDL and HDL are soaps.

 

The paper titled: Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults, shows that high mortality and disease occurs at either end of the "cholesterol" spectrum. This paper also shows that mortality and disease is much more pronounced at the low end, compared to the high end. In fact, the level that the American Heart Association considers optimal - and LDL < 70 mg/dL - is optimal - but not for good health - instead it is optimal for early death and disease.


This paper was published in 2019

 

What is low "cholesterol?"

A key paper on this topic was published in 1993.

It is old enough that it is not available as a text document so here are some screenshots.


***** NOTICE!! ***** This data is from our government !!!!

Several statement in this introduction stand out:

  • U-shaped association between blood cholesterol and subsequent mortality

  • The left side (low side) of this U represents increased mortality from cancer, pulmonary disease, digestive diseases, hemorrhagic stroke and accidental deaths (suicides are most predominant)

  • Cause for concern because it suggests outcomes of population interventions for cholesterol lowering that are opposite of intention

 
 

 

Possible causes of low cholesterol are:

  • statins

  • hyperthyroidism, or an overactive thyroid gland

  • adrenal insufficiency

  • liver disease

  • malabsorption (inadequate absorption of nutrients from the intestines), such as in celiac disease

  • malnutrition

  • abetalipoproteinemia - a rare genetic disease that causes cholesterol readings below 50 mg/dl.

  • It is found mostly in Jewish populations.

  • hypobetalipoproteinemia - a genetic disease that causes cholesterol readings below 50 mg/dl.

  • manganese deficiency

  • Smith–Lemli–Opitz syndrome

  • Marfan syndrome

  • leukemias and other hematological diseases

 

A paper titled, Hypolipidemia: A Word of Caution provides an overlapping list with more details....


Anemia Hypocholesterolemia has been described in various types of chronic anemia [1217]. Few studies have suggested that such patients have a lower incidence of atherosclerosis associated events [12]. Types of anemia that have been reported to be associated with hypocholesterolemia include: congenital dyserythropoietic anemia [12], congenital spherocytosis [12, 13], sickle cell anemia [14], beta-thalassemia [12, 15], aplastic anemia [16] and sideroblastic anemia [17]. The exact etiology of hypocholesterolemia in anemic patients is not known and the data are not sufficient, however several studies postulated different mechanisms [12, 1619], and some authors even suggest that hypocholesterolemia might be the cause rather than the consequence of anemia which is explained by the fact that cholesterol deficiency leads to rigidity of the erythrocytes [20] making them more prone to destruction. Hypocholesterolemia tends to occur in patients with chronic anemia and increased erythropoietic activity, and it has been suggested that this is due to increased cholesterol requirements by the proliferating erythroid cells [12]. Some researchers have demonstrated hypocholesterolemia in patients with aplastic anemia and correlated this with the elevated serum level of macrophage colony stimulating factor (M-CSF), which is known to have cholesterol-lowering activity, and they found that pretreatment total serum cholesterol and triglyceride levels nicely correlate with the counts of hemopoietic cells in the bone marrow. They concluded that low serum lipids suggest severe bone marrow failure in these patients and can help to predict the therapeutic response of each case of aplastic anemia [16]. Other researchers demonstrated a significant increase in serum cholesterol following splenectomy in patients with hypersplenism and preoperative hypocholesterolemia. They suggest a possible role of the spleen in lipid metabolism in these patients [19]. Bjerve et al reported a case of sideroblastic anemia and hypocholesterolemia due to autoantibodies against LDL causing an increased LDL catabolism [17]. Another animal study suggested that hypocholesterolemia in anemic mice is related to a decreased in vivo hepatic cholesterol synthesis [18].

Hyperthyroidism Thyroid disorders are known to affect lipid metabolism hence thyroid dysfunction may result in changes in the composition and transport of lipoproteins [21]. Both overt and subclinical hyperthyroidism is associated with reduced serum levels of TC, LDL and high density lipoprotein (HDL) [21, 22]. Hyperthyroidism can also be the underlying cause of unexplained improvement of hyperlipidemia [21]. These hypolipidemic changes in hyperthyroidism are explained by various effects of thyroid hormones on the lipoprotein metabolism. Despite the increased hepatic de novo cholesterol synthesis in hyperthyroid states due to augmentation of HMG-CoA reductase activity, levels of total and LDL cholesterol, are likely to diminish in patients with hyperthyroidism due to enhanced LDL receptor-mediated catabolism of LDL particles [21, 22] and increased bile excretion of cholesterol [21]. Moreover, the triiodothyronine (T3) enhances the gene expression of the LDL receptor and hence the receptor activity [21]. Thyroid hormones also stimulate the enzyme lipoprotein lipase (LPL), which catabolizes the triglyceride-rich lipoproteins [21]. The end result of all previous changes, is reduction in serum level of TC, LDL and HDL. However triglyceride levels remain unchanged [21], while the effect on lipoprotein (a) is still controversial, because both decrease or no changes have been reported [21].

Critical illness Total cholesterol levels drop at the onset of acute illness and return to normal during recovery [23, 24]. Multiple mechanisms influence hypocholesterolemia in critically ill patients and these include: downregulation of hepatic synthesis [25], probably due to decreased production of cholesterol precursors particularly lanosterol and lathosterol [26], loss of apoproteins in burns [27], and increased cholesterol catabolism [25, 28]. Low cholesterol concentrations associated with high levels of cytokines such as interleukin (IL)-6 and IL-10 [28], Hypocholesterolemia have been reported in patients with acute severe pyelonephritis [29], major trauma [24, 26], those with multiple organ dysfunction syndrome [25], burns [27], sepsis [30], and in patients undergoing surgical interventions [31]. More importantly, hypocholesterolemia is not only a marker for the disease severity but it may also predispose critically ill patients to sepsis and adrenal failure, and may carry a significantly increased risk of mortality. [23, 28, 30, 32]. In meningococcal septicemia, Vermont et al demonstrated that total cholesterol, HDL, and LDL levels on admission correlate inversely with disease severity and cortisol level [30]. The severity of hypocholesterolemia in sepsis is directly related to the severity of acute phase response [33]. In patients with major trauma Dunham et al demonstrated that hypocholesterolemia improves with recovery from acute illness but continues with development of organ failure or occurrence of infection [24].

Malignancy Several studies suggest an inverse relationship between serum cholesterol level and cancer mortality in patients with hematological and solid organ malignancies [3439]. Elevated LDL receptor activity in malignant cells may be a contributing factor to hypocholesterolemia in some cancer patients [38]. The evidence relating hypocholesterolemia to increased risk of cancer is controversial. In a large prospective study of Japanese-American men followed for >20 years, hypocholesterolemia was associated with increased risk of colonic cancer development; this relationship becomes stronger as the site of cancer shifts from the left to the right colon. The authors suggest that the preclinical effects of occult colonic cancer is responsible for this inverse relationship, but these effects do not explain why the association with hypolipidemia was stronger in patients who were later diagnosed with right-sided colon cancer [39]. Swanson et al also thought that hypocholesterolemia might be a predisposing factor for endometrial cancer [37]. In a large Japanese study of 9216 persons, hypocholesterolemia was significantly associated with an increased risk of liver cancer [40]. Moreover, several animal experiments have found that statins are carcinogenic at blood concentrations similar to those achieved by doses commonly used to treat hyperlipidemia, the carcinogenicity may be due to the effects of statins on cholesterol [41]. Furthermore, some human studies also connected the use of lipid lowering drugs to cancer development. The cholesterol and recurrent events trial (CARE), showed a significant increase in breast cancer, particularly recurrences [42], while the trial of Pravastatin in elderly individuals at risk of vascular disease (PROSPER), concluded that the benefit from fewer cardiovascular deaths was counterbalanced by the significant increase in cancer mortality [43]. Although several recent studies give reassuring evidences regarding the safety of statins with respect to carcinogenicity up to 10 years [44] but this period remains relatively short compared with the medically accepted latency period for cancer of 20 years [45]. In conclusion, evidence regarding the carcinogenicity of hypocholesterolemia from clinical studies in humans is inconclusive because of conflicting results and unsatisfactory duration of follow-up. The available evidence does not significantly support a direct cause-effect relationship between hypocholesterolemia and cancer [46], rather, the data suggest that low cholesterol levels may serve as a “marker,” or prognostic indicator of the disease [47].

Malabsorption Since dietary fats constitute the exogenous source of body lipids, undernutrition or fat malabsorption can lead to hypolipidemia. Brar et al demonstrated that celiac disease is associated with hypocholesterolemia and a gluten-free diet will result in rising of total cholesterol and HDL [48]. In patients with chronic pancreatitis, cholesterol absorption is markedly reduced primarily due to reduced intestinal lipolysis [49]. Bile acid malabsorption was also named as an additional factor in the development of hypocholesterolemia in patients with chronic pancreatitis [50]. Malabsorption is a common finding in patients with acquired immunodeficiency syndrome (AIDS) and fat malabsorption could be a contributing factor to the disease associated hypocholesterolemia. The pathogenesis of malabsorption in AIDS patients is multifactorial including primary enterocyte injury and exudative enteropathy [51].

Infection Acute and chronic bacterial, viral, and parasitic infections all might induce hypocholesterolemia due to the chronic effect of proinflammatory cytokines on lipoprotein metabolism. In 1911, Chauffard et al were the first to report hypocholesterolemia in patients with tuberculosis. Since then, transient hypocholesterolemia and hypertriglyceridemia were frequently observed during the acute phase of bacterial infections [52]. In 1920, Kipp noted an association between the degree of hypocholesterolemia and the severity of infection [1]. These changes are mediated by different cytokines as IL-1 and tumor necrosis factor-alpha (TNF) which are involved in the acute phase response during sepsis [52]. In critically ill patients, decreasing cholesterol levels suggest the development of infection. Some authors believe that hypocholesterolemia is a more sensitive marker for the onset of infection than leukocytosis [24]. Moreover, hypocholesterolemia was significantly correlated with the intensity of the acute phase responses during sepsis (as C-reactive protein level) [52]. Since parasites need to feed on host cholesterol for a successful infection [3], theoretically parasitic infestation might cause low plasma cholesterol. Several authors have shown that hypocholesterolemia has the strongest positive predictive value (96%) of the biological parameters for malaria diagnosis, [53]. Visceral lieshmaniasis also has been reported to cause hypocholesterolemia [54]. Human immune deficiency virus (HIV) is associated with hypocholesterolemia during the asymptomatic phase and is associated with specific alterations in immune function, suggesting that hypocholesterolemia may be a useful marker of disease progression [4, 55]. Hepatitis-C virus (HCV) is associated with significantly lower cholesterol levels (TC, LDL and HDL) when compared with those of normal subjects. Levels of apolipoprotein B (apoB) correlate negatively with HCV viral load and this finding is more pronounced in patients infected with HCV genotype 3 [56, 57]. In a Japanese study, infection with genotype 1b was also associated with hypocholesterolemia [58]. It was postulated that hypobetalipoproteinemia associated with HCV is mediated by HCV core protein, which down-regulates triglyceride metabolism, leading to steatosis [59]. Clinically, hypocholesterolemia in genotype 3 is associated with a more severe steatosis, and higher grades of fibrosis pointing out a more aggressive disease [60]. It also increases the risk of hepatocellular carcinoma [61]. From the previous studies one can suggest that the presence of acquired ApoB deficiency in HCV-infected patients may be used as an indication for treatment of HCV as it is likely to be associated with a more progressive disease.

Chronic liver disease Because hepatocytes are the most active site of lipid metabolism, hypolipidemia is frequently observed in severe chronic hepatic insufficiency [8]. A low serum cholesterol level is associated with a higher mortality rate in patients with liver cirrhosis [8, 62]. Advanced chronic liver disease can cause a reduction in apolipoprotein A and apolipoprotein B levels. Isolated deficiency of apolipoprotein B indicates abetalipoproteinemia or familial hypobetalipoproteinemia; which can result in liver involvement in the form of elevated transaminases, fatty liver and cirrhosis, while deficiency of both apolipoprotein A and apolipoprotein B is a manifestation of advanced chronic liver disease regardless of the etiology [63].

Chronic inflammation Changes in plasma lipid levels are a well known phenomenon in the acute phase response to inflammation. Chronic inflammation also can produce hypocholesterolemia due to the chronic effect of proinflammatory cytokines on lipoprotein metabolism. Ettinger et al demonstrated that chronic IL-6 injection causes acquired hypocholesterolemia in nonhuman primates [64]. Bologa et al found a significant relationship between TNF and IL-6 and the degree of hypolipoproteinemia in hemodialysis patients [65]. Ripollés et al have demonstrated that serum cholesterol was significantly lower in patients with active inflammatory bowel disease than in the control group [66]. Hypocholesterolemia also has been reported in patients with rheumatoid disorders [67]. Moreover, the anorexia that accompanies the chronic inflammatory disorders may contribute to the hypolipidemic effect of the proinflammatory cytokines in producing hypolipidemia in these conditions.

 

Consequences of hypolipidemia

1- Effects on plasma membrane Since about 44% of the human cell membrane is composed of lipids, they serve as a major structural component. Cell membranes are absolutely essential for the cell survival as well as for biological functions [68]. It is not known how very low plasma cholesterol levels would affect membrane composition and function but some indirect evidence might shed some light on this issue. Acanthocytes are dense, contracted red blood cells with several irregularly spaced thorny projections on the surface due to abnormal membrane fluidity. Acanthocytosis is a known clinical feature of abetalipoproteinemia and was also reported to be associated with hypolipidemia in celiac disease. In the later case acanthocytes disappeared two weeks after initiation of gluten free diet [69]. Acanthocytosis was also reported with hypobetalipoproteinemia in advanced chronic liver disease [63]. The exact mechanism of formation of acanthocytes is unclear, but reversal of the usual phosphatidylcholine-sphingomyelin ratio is considered to be a possible mechanism [70]. In a recent animal study, the hypolipidemic agent Atorvastatin caused significantly lower cholesterol and higher phospholipid content of red blood cell membrane, thus decreasing the cholesterol to phospholipid ratio. Although these structural changes were not associated with any obvious adverse rheological alterations, but they show that hypolipidemia may be associated with cell membrane lipid changes [71]. 2- Intracerebral hemorrhage (ICH) Intracranial hemorrhage accounts for approximately 10% of all strokes, and carries a significantly high morbidity and mortality as the 30-day fatality rate reaches up to 50% [72]. Several studies have demonstrated that low cholesterol is a risk factor for ICH [7375]. Others have reported that hypercholesterolemia is protective against ICH [7678]. Iribarren et al [74] described the association between low serum cholesterol level and cerebral hemorrhage in elderly men. In another study of young patients hypocholesterolemia (</=160mg/dl) was found in 35% of the patients with ICH compared to only 13% having hypertension [7]. Hypocholesterolemia was more common in ICH patients aged <20 years and in those with cryptogenic ICH [7]. Other authors have mentioned hypocholesterolemia <160mg/dl (4.14 mmol/l) as a contributing risk factor for Hypolipidemia intracerebral hemorrhage in previously healthy people [75]. The causal relationship is unclear; however, some investigators have proposed that the interaction of high diastolic blood pressure and low cholesterol levels weakens the endothelium of the intracerebral arteries [75], while another study reported platelet hypoactivity is associated with hypocholesterolemia [79], therefore affected patients may be more prone to bleeding. 3- Adrenal failure Cholesterol molecules are the precursors for adrenal steroid hormones. The adrenal gland requires a continuous supplement of cholesterol for the biosynthesis of adrenal corticosteroids, which can be supplied by LDL receptor-mediated uptake or through local synthesis [80]. Thus, at least theoretically; hypocholesterolemia will be associated with hypocortisolemia, and during stress cortisol production may not be high enough to protect against the cell damage. Hence critically ill patients will be predisposed to adrenal failure [23, 30, 81]. Although few human and animal studies support this hypothesis [30, 81], several authors have shown that in reality this does not happen [80, 82, 83]. Animal studies of the hypolipidemic drug Nafenopin have shown that despite significant lowering of serum cholesterol levels, this failed to alter blood corticosterone [82] and aldosterone [83] concentrations. This is probably because of the increased endogenous cholesterol synthesis as a result of compensatory smooth endoplasmic reticulum hypertrophy [82, 83]. Furthermore, one study of adult patients receiving 80 mg of the potent HMG CoA reductase inhibitor Simvastatin for two months showed that despite a 36%, reduction in total cholesterol level, there was no adverse effect on ACTH-stimulated adrenal corticosteroid production [80]. In summary; the available evidence is insufficient to support or refute the hypothesis that hypocholesterolemia can lead to adrenal failure. 4- Sepsis Hypocholesterolemia in healthy men is reported to be associated with significantly fewer circulating lymphocytes, total T cells, and CD8+ cells [84], thus the host immunity will be altered and the patient may be prone to infection. Harris et al reported that lipoproteins bind to and neutralize bacterial endotoxin lipopolysaccharide (LPS) [85]. LPS binds to LPS binding protein [86], activating the cell surface CD14 receptor [87] which stimulates the release of several proinflammatory cytokines, including TNF, IL-1, and IL-6 [88]. If LPS binds to lipoproteins, then cytokine release is decreased [89]. It is assumed that hypolipidemia impairs the LPS neutralization, hence predisposing to more severe inflammation. Recently Kitchens et al [90] demonstrated that despite hypocholesterolemia, circulating lipoproteins maintain their ability to bind and neutralize LPS. However in spite of this recent contradiction this issue remains unsolved as evidence remains inconclusive. Several authors report that hypocholesterolemia may be a predisposing factor to sepsis in the critically ill patient [23, 30]. A significant relationship has been observed between preoperative hypocholesterolemia and incidence of postoperative septic complications. Leardi et al reported that the highest incidence of postoperative septic complications is seen in patients with cholesterol levels below 105 mg/dl [10]. Moreover, a very low level of cholesterol is also considered to be a prognostic factor during infection, predicting an unfavorable outcome in elderly patients [52]. Hypocholesterolemia is the most frequently observed laboratory finding in fatal cases of pneumonia in the elderly [91], in a study conducted at a nursing home; hypocholesterolemia was the only admission feature associated with death due to bacteremia [2]. Pacelli et al reported hypocholesterolemia as an independent predictor of death in patients with intra-abdominal infection [92]. In neutropenic patients with fever, non-survivors had significantly lower serum cholesterol levels compared to survivors [93]. From these whole data one can conclude that hypocholesterolemia is a risk factor for infection in certain conditions as well as a prognostic indicator during sepsis. 5- Disease mortality Studies suggest that lipoproteins play a role in the binding and neutralization of endotoxins [85]. Epidemiologic studies have identified a relationship between hypocholesterolemia (<130 mg/dL) and increased mortality from all causes [14]. Crook et al stated that, in hospitalized patients the lower the plasma cholesterol the higher the mortality, and they demonstrated an increase in the mortality rate from 39% to 71% as plasma cholesterol dropped from <77.2mg/dl (2mmol/dl) to <58mg/dl (1.5 mmol/l) [11]. A low baseline serum cholesterol level is associated with higher mortality rates in patients with liver cirrhosis. There is a significant relationship and increased risk of mortality in patients with HIV and HCV co-infections [62]. Hypocholesterolemia is also associated with increased mortality in patients with tuberculosis [94]. Several epidemiological studies suggest an inverse relationship between serum cholesterol levels and cancer mortality [34]. Following a severe trauma, dying patients appear to have progressive hypocholesterolemia [24]. In conclusion, hypocholesterolemia has a statistically significant relationship to mortality in the critically ill patient and is an independent predictor of mortality in this group.

 

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Jeremy Stollings
Jeremy Stollings
26 de mar. de 2021

Thank you for the excellent write up on this topic! We appreciate the work you are doing and thank you for sharing!

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