Diabetes Liver Disease - NAFLD and NASH
Before considering the bad news about Diabetes 2, the reader should understand
that diabetes 2 and all its complications is an optional disease process. Each
person who has or is heading for diabetes 2 has choices. The only logical
conclusion is that wrong food and too little exercise will lead you down a path
of misery and progressive deterioration. A collection of metabolic problems is
found in patients with type 2 Diabetes. This metabolic syndrome involves insulin
resistance, gout, hypertension, android (visceral) obesity, hypertension,
hypertriglyceridemia, hyperbetalipoproteinemia and low concentrations of the
protective blood fat, HDL. These metabolic problems are all risk factors for
liver disease, atherosclerosis, coronary artery disease and strokes.
According to the National Diabetes Information Clearinghouse (a service of
the National Institute of Diabetes and Digestive and Kidney Diseases, U.S.
Public Health Service.): "Diabetes is widely recognized as one of the leading
causes of death and disability contributing to the deaths in the USA alone of
more than 169,000 persons in 1992. Its toll increases every year. Diabetes is
associated with long-term complications that affect every part of the body.
The main horrors are Liver Disease (NAFDL and NASH), blindness, heart disease,
strokes, kidney failure, amputations, and nerve damage.
In one study, 40- to
89-year-old people were followed for a decade. Individuals with type 2 diabetes
were more likely than nondiabetic individuals to be hospitalized for or die from
chronic liver disease. These were defined as alcoholic liver disease, autoimmune
liver disease, hemochromatosis, hepatocellular carcinoma, nonalcoholic fatty
liver disease (NAFLD; including cirrhosis and hepatic fibrosis), and viral liver
disease. Diabetic men were three times
more likely than other men their age to be hospitalized for or die from NAFLD —
the most common type of liver disease in diabetic patients — whereas this was
five times more likely to occur in diabetic versus nondiabetic women of the same
age. (Wild SH et al Type 2 diabetes and
risk of hospital admission or death for chronic liver diseases J Hepatol.
2016. January 23, 2016 )
Fatty Livers NAFLD
Fat accumulates in livers for a variety of reasons. For many years,
alcoholic liver disease was the most prevalent diagnosis. More recently, a large
and growing population of obese and diabetic patients have fatty livers
associated with inflammation, scarring. The term “nonalcoholic fatty liver
disease (NAFLD)” is often used in the medical literature. A better term
would be fatty liver disease (FLD); the reference to alcoholics is no longer
appropriate. McNear and Harrison
stated: ” FLD is currently the most common form of chronic liver disease in
the world with a prevalence estimated to be around 30% in the US.
The prevalence in diabetics is up to 63% and in the morbidly obese
undergoing bariatric surgery up to 93%. FLD may effect any age and
demographic, with only a slight variation in risk. Within the spectrum of FLD,
isolated fatty livers appear to be a rather benign disease with minimal risk of
progression to advanced liver disease, but there has been an association with
increased all-cause mortality, liver-related death and cardiovascular disease.
Elsheikh et al wrote: "Nonalcoholic fatty liver disease (NAFLD)
is rapidly becoming the most common form of chronic liver disease in the Western
world and is increasing in importance in other parts of the world. NAFLD
comprises a spectrum of liver damage including in its common form, or
simple steatosis, as well as nonalcoholic steatohepatitis (NASH), a potentially
progressive form of NAFLD defined by the presence steatosis as well as
hepatocyte ballooning, inflammation and variable degrees of fibrosis. "
A 'fast-food diet,' high in fat and sugar, seems to exacerbate development
of FLD. The high fructose content in sugar-sweetened beverages, and the high
trans-fat content in fried and highly processed foods, may be particularly
damaging. Sedentary adults who ate two fast-food meals a day for 4 weeks had
significant increases in liver fat and in serum alanine aminotransferase.
Diabetic Steatohepatitis NASH
Diabetic SteatoHepatitis (DSH aka NASH) is a more aggressive
form of hepatic disease with the development of varying degrees of
inflammation, fibrosis and possible progression to cirrhosis, end-stage liver
disease and hepatocellular carcinoma. The historical prevalence of NASH is 3-5%
however, this is likely a current underestimation, as the prevalence of DSH has
been shown to be >35% in obese patients undergoing bariatric surgery.”
Elsheikh et al wrote: "The presence of obesity at least doubles
the prevalence of NASH and its progression to cirrhosis, liver failure and
hepatocellular carcinoma... The resultant steatosis (fat deposition and
accumulation) in the liver may result from four distinct processes: increased
delivery of free fatty acids( FFAs) to the liver; increased de novo synthesis of
free fatty acids (FFAs) in the liver; decreased oxidation of FFA and
decreased synthesis or secretion of VLDL... insulin stimulates postprandial
glucose uptake and FFA esterification in the adipocytes and hepatocytes and
suppresses hormone-sensitive lipase in the adipose tissue. In the presence of
Insulin Resistance, there is an increase in lipolysis and the release of FFAs
from the adipose tissue."
Purito et al stated:" Evidence implicates lipid in the form of free fatty
acids (FFAs) as the major mediator of liver injury in NASH. A 'lipotoxicity'
model suggests that hepatic steatosis and inflammation develop concurrently.
Some FFAs are trafficked into intrahepatocyte triglyceride droplets, leading to
steatosis. FFA metabolites not sequestered as triglycerides promote apoptotic
and inflammatory pathways, for example, by activating toll-like receptor 4
ligands or destabilizing lysosomes to induce cathepsin B release, both triggers
for apoptosis. Reactive oxygen species formed during FFA metabolism may
overwhelm mitochondrial antioxidant capacity, eliciting additional inflammation
and apoptosis. In this model, sequestering FFA in triglyceride droplets may
actually protect against inflammatory liver injury... The most effective
currently available treatment for NASH is lifestyle intervention to induce
weight loss, including dietary modification and increased physical activity. "
Sanyal et al studied 247 nondiabetic adults with biopsy-proven steatohepatitis (NASH) with an activity score of 4 or higher: 80
patients took pioglitazone 30 mg once daily, 84 took vitamin E 800 IU/day, and
83 received placebo. Liver biopsy was performed before and after
treatment. The Vitamin E group had the best outcome: improved steatosis,
inflammation, ballooning scores, and serum ALT, but no improvement in fibrosis
scores. Pioglitazone was less effective than vitamin E but superior to placebo.
Ashan et al expanded our knowledge of Vitamin E benefits to Tocotrienols, a relatively
unknown form of vitamin E activity. They stated: " Liver the largest glandular
organ of the body and the key organ of metabolism has a pivotal and immense task
of detoxification of xenobiotics, environmental pollutants and chemotherapeutic
agents. Hence this organ is subjected to a variety of diseases and disorders…
dietary antioxidants play an important role in the management of liver
disorders. Tocotrienols, members of the vitamin E family, are natural compounds
found in a number of vegetable oils, wheat germ, barley, and certain types of
nuts and grains. Like tocopherols, tocotrienols are also of four types viz.
alpha, beta, gamma and delta. Unlike tocopherols, tocotrienols are unsaturated
and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and
are found in association with lipoproteins, fat deposits and cellular membranes
and protect the polyunsaturated fatty acids from peroxidation reactions. The
unsaturated chain of tocotrienol allows an efficient penetration into tissues
that have saturated fatty layers such as the brain and liver. In prospective
liver transplantation patients, oral Tocotrienol (TE) lowered the model for
end-stage liver disease (MELD) score in 50% of patients supplemented, whereas
only 20% of Tocopherol-supplemented patients demonstrated a reduction in MELD
score. The results demonstrated that orally supplemented TE are transported to
vital organs of adult humans. The findings of this study, in the context of the
current literature, lay the foundation for Phase II clinical trials testing the
efficacy of TE against stroke and end-stage liver disease in humans. All these
findings are very promising and demand the attention of the scientific community
for further exploration and evaluation of tocotrienols against hepatic toxicity.