About GGT (Oracle of Death or The final common Pathway) | Reverse Diabetes MD from Gurpreet Padda on Vimeo.

Excess processed foods and carbohydrates can also lead to increased liver damage. GGT isn’t something that people consider when considering health risks, but it could be referred to as the “oracle of death” or “the final common pathway” because of how it predicts liver damage and subsequent disease. Gamma-glutamyl transferase (GGT) is an enzyme found in high concentrations in the liver, and it is elevated in diseases that cause damage to the liver.

GGT is a transferase that catalyzes the transfer of gamma-glutamyl functional groups from molecules such as glutathione (GSH) to an acceptor that may be any amino acid, a peptide, or water. GSH removes free radical toxins and provides natural protection against harmful oxidative stress. The normal biologic role of GGT is to reconstitute glutathione, the body’s master antioxidant.

GGT is the only enzyme of the GSH cycle located on the outer surface of the plasma membrane. It breaks down extracellular GSH and provides cysteine, the rate-limiting substrate, for intracellular de novo synthesis of GSH. When GGT concentrations are above “low-normal” ranges, excess GGT can catabolize (degrade) GSH, causing critical depletion of this antioxidant.

When GSH is depleted, oxidative stress and damage start to occur.  This leads to lead to a cycle of the irreversible cell, tissue, and DNA damage, and severe impairment of organ function. Elevated GGT indicates that you are demanding more GSH, and there was not enough GSH in the system to deal with an oxidative insult. During oxidative stress, GGT gene expression is increased, an adaptation to stress.

If you consume excess carbohydrates, processed foods, vegetable oil, alcohol, or other liver toxins, the liver can become insulin resistant, resulting in a high insulin level. Elevated insulin is a metabolic switch that causes fat to accumulate in the liver. Hyperinsulinemia (excess insulin) drives insulin resistance, and insulin resistance encourages more hyperinsulinemia.

As fat accumulates in the liver, the liver becomes more insulin resistant and simultaneously undergoes more oxidative stress, depleting Glutathione, which is reflected by increasing GGT.

 

GGT data was originally collected by the smartest guys in the room (life insurance actuaries), and the original reason for measuring it was its ability to mark alcohol abuse in life insurance applicants. The life insurance industry collected this data for many years, resulting in biometric stratification of mortality risk, and it has now become central to the life insurance underwriting process for predicting all causes of death.

Palmier J., Dixon A., Lanzarth B. Leading Contributors to Mortality Risk in Life Insurance Applicants. Schaumburg, Ill, USA: Society of Actuaries; 2012. (Smalltalk Issue 38).

Palmier J., Lanzrath B. J. Laboratory and biometric predictors of cancer-related mortality in an insured population. Journal of Insurance Medicine. 2012;43(3):162–168

 

Traditionally, elevated GGT has been associated with liver dysfunction, most often alcohol overconsumption. Other drugs that can elevate GGT include barbiturates, phenytoin, anti-inflammatory drugs (including aspirin), St. John’s Wort, and kava.

We now believe that elevated GGT is an early warning sign of other health risks, such as atherosclerosis, stroke, type 2 diabetes, kidney disease, cancer, metabolic syndrome (MetS), and all-cause mortality.

GGT doesn’t have to be above levels considered normal by a laboratory in order to have increased risks. When GGT concentrations exceed the lowest 25% to 35% of normal population ranges, disease risks grow in proportion to increased GGT. This “dose-response” increase in GGT concentration, indicates a greater risk of future diseases and mortality, even when GGT levels are within “normal” ranges.

Even a higher end of normal GGT poses a significant increase in risk:

Normal low

• < 9 U/l for women
• < 14 U/l for men

Moderately high with increased risk

• 18 U/I for women
• 28 U/I for men

High levels of normal with significant increase in risk

• >36 U/L for women
• >56 U/L for men

According to the National Institute of Health, “GGT levels measured in the Framingham Offspring Study (FOS), only moderately elevated GGT, starting at levels just above population GGT medians, and often measured one or two decades in advance of disease endpoints or mortalities, established GGT as an early predictive marker of MetS, CVD, heart failure, and all-cause mortality.”

 

Gamma-Glutamyltransferase: A Predictive Biomarker of Cellular Antioxidant Inadequacy and Disease Risk

Gerald Koenig, Stephanie Seneff. Dis Markers. 2015; 2015: 818570. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620378/

GGT is predictive of future mortality. In the general population, about 21% of men and 15.6% of women have elevated GGT. Elevated GGT, even within normal laboratory ranges, presents significant additional risks.

Patients with a high end of normal  GGT have more than a 1.5-fold risk of dying from cardiovascular diseases in comparison to people with normal low levels of GGT.

All-cause mortality and elevated GGT in the upper fifth of the population levels results in a 2x higher risk for all-cause mortality, 1.7x  higher risk for cardiovascular death, and 2.3x higher risk for cancer and death. Liver cancer and elevated GGT in the upper fifth of the population levels (not even top 1%) results in 15 to 18 times higher risk hepatic cancer and death from liver cancer

Hazard ratios

According to Clinical Chemistry, “GGT above the reference category (GGT ≥9 U/L in women, ≥14 U/L in men) was significantly (P <0.001) associated with all-cause, cancer, hepatobiliary, and vascular mortalities.”

Gamma Glutamyltransferase and Long-Term Survival: Is It Just the Liver? Lili Kazemi-Shirazi et al. DOI: 10.1373/clinchem.2006.081620 Published April 2007. http://clinchem.aaccjnls.org/content/53/5/940

Elevated levels also result in increased risk for atherogenic dyslipidemia, a predictor of impending heart disease. Dyslipidemia is a reflection of insulin resistance, and when your liver becomes insulin resistant, it will tend to cause visceral fat accumulation in your organs.  Visceral fat accumulation is most noticeably seen as a larger waist than expected, or a “beer belly,” even a small one in women.  Many people are apparently slim, but they are TOFI (thin outside, fat inside).

Dyslipidemia is a combination of high LDL, low HDL, high triglyceride, high particle count of LDL

• LDL:HDL
  Triglyceride:HDL
  LDL-P
  Oxidized LDL
  GGT

 

Most idiopathic or essential hypertension (where they don’t know the cause of the high blood pressure) – is related to hyperinsulinemia with resulting vessel stiffness and thickness.  Reversing hypertension may be as simple as reducing insulin.

GGT correlates with atherosclerotic plaque formation in arteries, which is associated with an inflammatory disease, metainflammation.

GGT activity also co- locates with oxidized LDL in the atherosclerotic plaque, as seen below.

Circulating Markers of Liver Function and Cardiovascular Disease Risk.

Arterioscler Thromb Vasc Biol. 2015 Nov;35(11):2290-6. doi: 10.1161/ATVBAHA.115.305235. Epub 2015 May 14.

https://www.ncbi.nlm.nih.gov/pubmed/25977566

Risk for future diabetes:

If your BMI is low and you have a low GGT, you have a baseline risk of 1.0

If you have a low BMI below 25 and a high GGT (in the top quarter of the population), you have a 3x risk of diabetes within 3-5 years

If you have a moderate-high BMI greater than 30 and a high GGT (in the top quarter of the population), you have a 15x risk of diabetes within 3-5 years

If you have a high BMI greater than 35 and a high GGT (in the top quarter of the population), you have a 19x risk of diabetes within 3-5 years

Obesity is one factor that predicts future diabetes, but GGT may be more accurate. If you correct the obesity level for GGT, obesity doesn’t predict diabetes. GGT is more predictive of diabetes as it reflects liver insulin resistance and liver inflammation.

Our treatment protocols for elevated GGT encourage:

• Decompress the fat out of the liver by either time-restricted feeding or fasting
• Eliminate vegetable oil and supplement with fish or krill omega-3 oil
• Switch to natural fats, such as butter and tallow
• Eliminate processed foods, including refined grains and acellular carbohydrates
• Metformin to enhance insulin sensitivity in the liver
• Moderate to high coffee consumption has been universally shown to reduce GGT