Nonalcoholic fatty liver disease (NAFDL): the overflow paradox
Nonalcoholic fatty liver disease, or NAFLD is the most common chronic liver disease in the world. It is present in 30% of the general adult population and exceedingly diagnosed in obese people with high carbohydrate diets and inactive lifestyles. NAFLD comprises a spectrum of hepatic abnormalities, from simple hepatic steatosis (accumulation of fats) and nonalcoholic steatohepatitis (inflammation), to fibrosis (thickening or scarring of the tissue), cirrhosis (degeneration of liver cells), and liver cancer.
While the pathogenesis and dynamics of NAFLD are tenably due to an interplay of poor diet, imbalances in microbiota (intestinal microbes) and genetic factors, a causal relationship is established between excessive sugar intake, hyperinsulinemia, and the onset of this disease.
Sugar, insulin and the liver
When we ingest sugars and all types of non-fiber carbohydrates, they get broken down by digestion into glucose molecules - their Lego pieces, so to speak. As is the case for all nutrients, carbohydrates get disassembled so they can be immediately used as quickly dissoluble fuel for energy, or re-assembled as needed into more complex vital compounds. The rise of glucose concentration in the bloodstream from carbohydrate fragmentation prompts the pancreas to produce insulin, a peptide hormone whose primary task is to grab the floating glucose molecules and haul them into liver cells (hepatocytes), adipose and muscle cells, to be burned for everyday energy needs.
Insulin is an anabolic hormone - it holds on to, assembles and stores nutrients, in fact it promotes protein synthesis in muscle cells, which is good news for bodybuilders. In carbohydrate metabolism, insulin routinely spares the glucose that is not immediately used for fuel by storing it in the liver and muscle cells, in the form of a sugar polymer (polysaccharide) called glycogen, which is basically a reservoir of glucose, and in the form of fat, as adipose tissue. Both glycogen and fats are fuel reserves our body has access to for energy while in a fasted state, since due to the demands of the tissues and organs, blood glucose levels must be maintained in the normal range of 80–120 mg/dl. In response to a drop in blood glucose concentration, once insulin drops, blood fuel homeostasis is restored primarily by two energy-producing pathways that mobilize those reserves: hepatic glycogenolysis, which is the breakdown of glycogen reserves to supply glucose, and lipolysis, or breakdown of stored fats.
Inside the liver, insulin also turns on a process called Hepatic de novo lipogenesis (DNL), the biochemical process of synthesizing fatty acids from acetyl-CoA, an important molecule in metabolic processes which is also a by-product of carbohydrate catabolism (breakdown). In addition to glucose, which most commonly supplies carbon units for DNL, fructose is also a potent lipogenic (fat producing) substrate that can crank up DNL, important when considering the widespread use of fructose as a processed food sweetener, as either high fructose corn syrup or disguised under euphemistic chemical names that deceive label readers.
Along with glucose made from glycogen stores, when insulin drops in a fasting state, the liver increases its secretion of fatty acids into the bloodstream in the form of triglyceride-rich lipoproteins called VLDL. In actual fact, and crucial to this discussion, the storage of excess lipids is not among the physiologic functions of the liver, which normally is almost devoid of fat content from adequate releasing. Under normal circumstances, the liver routinely processes large quantities of fatty acids, but stores only small amounts in the form of triglycerides, with steady state triglyceride contents of less than 5%. To sum all of this up: a rise of insulin, when we eat, shuttles glucose into liver cells, which are prompted by insulin to make fat from it; a drop in insulin levels, when we are fasting, signals the liver to let reserves of sugar and fatty acids out. That being the case, as long as we balance feeding states with fasting states, everything unfolds as intended. Problems start when our intake of sugars exceeds our needs: in the setting of overnutrition and obesity, liver fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes (fat cells in the liver), and to NAFLD.
Hyperinsulinemia and NAFLD: the metabolic paradox
The genesis of NAFLD and insulin resistance, a condition in which cells in the body, including hepatic cells, begin rejecting insulin, (because, very simply, they have too much glucose as it is), with the ensuing compensatory hyperinsulinemia, which occurs when the pancreas increases insulin production in an effort to send reinforcements, are all interconnected in a vicious cycle.
NAFDL is described as an overflow condition, in which the liver increases fatty acid production, and in an effort to off-load the hefty lipid cargo, as well as to replenish plasma energy fuel when glucose levels drop, it increases the export rate of fatty acids into the bloodstream. These fats are then directed to and stored in adipose tissues, causing weight gain. There is an obvious incongruity in all of this: the liver isn’t taking up anymore glucose to use for the DNL, yet it is burgeoning with fats and constantly spewing them out. This happens because of both insulin resistance and hyperinsulinemia: while glucose entry mechanics are downregulated, de novo lipogenesis is upregulated by persistently circulating insulin through a transcription signal. In a post-absorptive state, as soon as insulin drops (as previously discussed), the liver attempts to release as much fat load as possible into the bloodstream in the form of triglycerides, LDL and other types of fatty acids. In short, while cells are starved for nutrients and energy from not being able to let all the glucose in, the liver is making fatty acids at an increasing rate under that constant insulin stimulation, and ballooning to accommodate all that fat. This is what is known in medicine as an overflow paradigm, and it is the paradox that explains metabolic syndrome and Type 2 Diabetes, in which malnutrition and obesity coexist.
It is worth noting, and relevant to diagnostic accuracy, that lower fasting triglyceride levels may paradoxically indicate more advanced liver disease. Researchers have found that as liver disease progresses, patients may develop hepatocellular dysfunction that impairs triglyceride production, resulting in lower than normal triglyceride levels. This is why a thorough clinical examination is important when central weight gain, high blood pressure, low HDL, high inflammatory blood markers and other metabolic disruptions are present.
Hepatic steatosis is consistently one of the most important markers of insulin resistance. The degree of insulin resistance is directly related to the amount of fat in the liver. However, it bears emphasizing that NAFLD has been defined as a ‘multi-hit’, vicious circle condition, in that factors such as oxidative stress, gut bacteria endotoxins, iron overload and pro-inflammatory cytokines may all be conducive to and/or be caused by accumulation of triglycerides; these factors all contribute to the advancement of NAFLD to nonalcoholic steatohepatitis, or NASH, which presents with various degrees of necrotic inflammation, fibrosis and cellular death. For these reasons, a comprehensive nutritional approach is key to reversing the condition.
NAFLD as a marker of Metabolic Syndrome, Type 2 Diabetes and cardiovascular disease
Metabolic syndrome is a cluster of interrelated cardiovascular risk factors including obesity, insulin resistance, hyperinsulinemia, hypertension, dyslipidemia and consistently elevated plasma glucose. Obesity, defined as having a BMI >30, is associated with insulin resistance, as it is both a cause and a consequence of it, and with hepatic steatosis. The presentation of metabolic syndrome happens in sequential steps: 1. moderate weight gain; 2. low HDL; 3. hypertension; 4. NAFLD and high triglycerides; 5. high plasma glucose, the last marker to appear.
Evidence from epidemiological studies has shown NAFLD and high triglyceride count precede the diagnosis of Type 2 Diabetes, or T2D, by at least 18 months, proving that accrual of liver fat is a major determinant in the development of insulin resistance, hence the onset of T2D. NAFLD prevalence ranges from 50%–75% in subjects with type 2 diabetes, and, according to different studies, from 80%–90% in obese subjects.
Though the disease seems to be generally prevalent in men, there is a high incidence of NAFLD in post-menopausal women, possibly due to a higher incidence of metabolic complications due to estradiol deficiency and relative androgen excess. Menopausal hormonal changes, along with a decreased level of physical activity, cause an increase in abdominal adipose mass and speed cellular aging, two factors that raise the risk of developing NAFLD and may increase the severity of its course.
NAFLD, Omega 3s, vitamins A, D, E and K
The liver produces bile, a fluid substance containing organic salts and stored in the gallbladder, which breaks down fats enough to extrapolate fat-soluble essential nutrients like Omega 3 fatty acids and vitamins A,D, E and K. Production of bile in a fatty liver is impaired to different degrees, causing significant deficiencies in these nutrients. Symptoms of NAFLD can in fact be associated with this absorption pathway inefficiency, ranging from systemic inflammation to muscle weakness and generalized pain, vision problems, fatigue, anxiety, depression, low immunity and mineral imbalances.
NAFLD and hormonal imbalances
The liver participates in most steps of steroid hormone regulation, from the biosynthesis of cholesterol, which is the main source for steroid synthesis, to several conversion pathways, ending with toxic hormone waste detoxification. In individuals with an overburdened liver, such as in NAFLD, detoxification pathways are flawed, causing hormonal imbalances such as estrogen dominance, the underlying cause of many types of estrogen-sensitive cancers such as breast, ovarian, uterine and prostate. A decreased rate of estrogen excretion, coupled with several other imbalances such as low thyroid function, contribute to central obesity; in turn, adipose cells acts as endocrine factories that use androstenedione and an enzyme called aromatase to manufacture more estrogens, leading to a vicious cycle of fat storage and weight gain. Furthermore, estrogen dominance induces hypothyroidism, which can disrupt the balance between good and bad cholesterol and increase the amount of triglycerides in the liver, worsening the condition.
The importance of a nutrition and lifestyle intervention in NAFLD management
In conclusion, it is evident that a comprehensive nutrition and lifestyle intervention, aimed at improving all parameters of metabolic syndrome and reducing the risk of NAFLD, is paramount to preventing complications from this disease and reversing it. While study after study has proven NAFLD to be an independent risk factor (as in the absence of obesity, T2D and baseline risk factors), for cardiovascular outcomes such as ventricular dysfunctions, atherosclerosis and ischemic events, it is still clinically treated as a benign condition with outdated therapies.
Testing for NAFLD
Since it is mostly asymptomatic in its early stages, NAFLD must be diagnosed by clinicians who suspect liver damage while testing for related conditions, such as insulin resistance, dyslipidemia or diabetes. Testing is advisable for overweight individuals or people whose daily intake of processed foods, and more specifically fructose-laden foods, would clearly point to an increased chance of developing the condition.
Blood testing is done to detect the presence of the liver enzymes below (reference ranges are in brackets), which are released either in excess or less than mean amounts into the bloodstream by a damaged liver:
Alanine transaminase (ALT), that helps convert proteins into energy for the liver cells [NR (normal range) 7 to 55 units per liter, or U/L]
Aspartate transaminase (AST), an enzyme that helps metabolize amino acids [NR 8 to 48 U/L]
Alkaline phosphatase (ALP), an enzyme that breaks down proteins, whose presence in the blood may signal a blocked bile duct or bone disorder [NR 40 to 129 U/L]
Albumin and total protein. Albumin is one of the proteins made in the liver, needed to fight infections and for other biological functions [Albumin NR 3.5 to 5.0 grams per deciliter (g/dl); Protein NR 6.3 to 7.9 g/dl]
Bilirubin, the brownish/yellowish waste product of hemoglobin breakdown; it passes through the liver and gets excreted into the bile, and it is what causes a condition known as jaundice [NR 0.1 to 1.2 mg/dl]
Gamma-glutamyltransferase (GGT), present in all organs and in the highest concentration in the liver; usually the first liver enzyme to rise in the blood when any of the bile ducts become obstructed [NR 8 to 61 U/L]
L-lactate dehydrogenase (LD), involved in energy production, used to detect tissue damage, cellular destruction or fluid disorders [NR 122 to 222 U/L]
Prothrombin time (PT), which is simply the time it takes your blood to clot. Increased PT may signal liver damage but can also be elevated in individuals on blood-thinners [NR 9.4 to 12.5 seconds]
Imaging Procedures:
Abdominal ultrasound
Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the abdomen
Transient elastography
Magnetic resonance elastography
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References:
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