New Recommendations Call for Standard ALT Screenings

From the American Association for the Study of Liver DiseasesAlarming Evidence Shows Elevated ALT Ups Mortality by 60%

BOSTON—Knowing your alanine aminotransferase (ALT) level, like knowing your blood pressure, fasting blood glucose, hemoglobin A1c, and cholesterol levels, should become part of basic personal health awareness, according to new recommendations from the American Association for the Study of Liver Diseases (AASLD) that were presented at the association’s annual meeting.

ALT, a protein made predominantly in the liver, participates in the modification of amino acids. Mounting evidence from population-based studies has documented a strong association between elevated ALT levels and subsequent mortality. Mortality rates jump by 60% to 80% when ALT goes beyond twice the upper limit of normal, with the risk further magnified among women.

Adrian M. Di Bisceglie, MD, chief of hepatology, Saint. Louis University School of Medicine, and chairman of public policy for the AASLD, said at the meeting that abnormal ALT activity is often ignored or minimized by physicians who construe them to be clinically insignificant in asymptomatic patients. “Every raised ALT is worthy of examination,” he stated, “especially when it persists over 3 to 6 months.”

The American Liver Foundation estimates that 30 million Americans, knowingly or not, have liver disease. With the epidemic rise in the prevalence of obesity and metabolic syndromes, the most common cause of ALT elevations in North America is fat accumulation within liver cells, known as non-alcoholic fatty liver disease (NAFLD). Fat accumulations in the liver are toxic. Other causes of ALT elevations include excessive alcohol consumption, chronic hepatitis virus infection, drug toxicity, and genetic and autoimmune liver diseases.

“Also of great concern is a new message emerging over the last 3 to 4 years that the mortality risk is raised with elevated ALT, not only in liver disease but also in non—liver-related ailments, particularly cardiovascular disease,” Dr Di Bisceglie said. “A persistently raised ALT is a symptom that one’s body is sick, usually because one is overweight or on the way to diabetes.”

Dr Di Bisceglie estimated that in any group of 100 patients with raised ALT levels, about:

• 30-40 would have NAFLD

• 10-20 would have hepatitis

• 5-10 would have alcohol-related increases

• 5 would have bile duct disorders

• 5 would have autoimmune liver diseases.

Finally, in about 15 to 20 patients, raised ALT would be related to drugs and medicines. The etiology is unknown in others.

Among the drugs most likely to cause acute liver injury, acetaminophen can be the most dangerous, because of its toxicity at relatively low doses, especially in those with high alcohol consumption. This drug and others with liver-harming potential (eg, anticonvulsants, antibiotics, and statins) account for 80% of drug-related liver toxicities.

What then is an elevated ALT level? The lack of standardization among laboratories, Dr Di Bisceglie conceded, is part of the problem. Different labs can define anywhere from 40 to 65 U/L as normal. “Unfortunately,” he said, “their samplings conducted to determine what is normal can include high proportions of overweight patients with a bit of fatty liver disease that push the normal range up. That’s why we need an effort to create a national standard.” A level of 60 U/L should be considered mildly ele-vated, he says.

The new recommendations call for making ALT a standard screening metric and requiring further investigation when abnormal levels are detected. “It is not a fancy test, but simply part of the standard multiphasic panels included with the blood test,” he noted.

The important point is that many liver diseases can be treated when they are caught early. “We don’t want physicians to ignore ALT elevations, because they very often are a flag for potentially serious liver disease,” Dr Di Bisceglie emphasized.

Elevated ALT Levels Predict Risk of Death From Liver Cancer

November 2, 2006 (Boston) — The currently accepted upper limit of normal for serum alanine aminotransferase (ALT) levels is “artificially high,” officials from the American Association for the Study of Liver Diseases (AASLD) believe. The current normal range excludes a number of individuals who feel well but who are at increased risk for liver disease.

AASLD officials are working to “recalibrate” the normal range, based in part on a number of studies presented here this week at the AASLD 57th annual meeting, which show that elevated liver enzymes are a risk factor for mortality in general and liver disease, specifically.

Elevated serum aminotransferases, such as ALT and aspartate aminotransferase (AST), predict mortality in the general population, according to W. Ray Kim, MD, associate professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota.

Dr. Kim presented data on 18,330 community residents who had AST levels measured at least once in 1995. Of these, 15,991 had normal results and 2339 had elevated AST levels.

Also in 1995, 6792 residents had ALT levels measured, and of these, 907 had elevated values.

Dr. Kim reported “a significant increase in the standardized mortality ratio with increasing AST and ALT levels, whereas a normal AST or ALT level was associated with a risk of death lower than expected.”

AST levels 2 times the upper limit of normal had a mortality ratio of 1.79 and ALT levels 2 times the upper limit of normal had a mortality ratio of 1.63. There was “a near-linear relationship between AST and ALT values and subsequent risk of death in both genders,” Dr. Kim showed.

He suggested that AST and ALT screening be a part of the general medical evaluation of patients. “[Elevated] ALT may identify patients at risk of death from liver disease early in their disease,” he told AASLD meeting attendees.

Dr. Kim’s study was independently funded. Dr. Kim reported no relevant financial relationships.

In a separate study, John McHutchison, MD, director of gastroenterology and hepatology research at Duke University Medical Center in Durham, North Carolina, and colleagues presented data on an investigational agent, PF-03491390 (Pfizer Ltd, Sandwich, UK), used in chronic active hepatitis C virus (HCV) infection.

The agent, a pancaspase inhibitor, lowers elevated ALT and AST levels by blocking apoptosis of hepatocytes.

The dose-ranging study involved 204 patients with chronic active HCV infection and liver fibrosis, who were randomized to placebo, 5 mg, 25 mg, or 50 mg of PF-03491390 twice a day orally for 12 weeks.

If ALT and AST levels were still elevated at week 10, the dose was doubled for the remaining 2 weeks.

Reductions in both liver enzymes were seen within the first week of treatment and were sustained throughout. Reductions were dose-related in a linear fashion.

Adverse events were primarily mild or moderate, with headache and fatigue reported in 24 and 22 patients, respectively, the most common.

The pancaspase inhibitor did not affect HCV RNA levels.

Dr. McHutchison’s study was funded in part by Pfizer, Ltd, Sandwich, UK. He has also received funding grants from Vertex Pharmaceuticals, Inc, GlaxoSmithKline, and Coley Pharmaceutical Group, Inc, for other research.

AASLD Chairman of Public Policy Adrian DiBisceglie, MD, chief of hepatology at St. Louis University School of Medicine in Missouri, told Medscape that the association is in the process of “recalibrating” the ALT normal range.

“We are setting [upper] limits lower than they have been to include people with abnormal ALT levels who feel well but who still have an increased risk of liver disease,” he said. Setting the upper limit of normal lower will decrease the specificity some, but it will increase the sensitivity.”

Upper limits of normal range from 30 IU/L to 60 IU/L, depending on the laboratory. “We want to reset it southward of 30 IU/L,” Dr. DiBisceglie said.

“ALT levels are a reflection of the general vascular condition,” he said. “If the level is above 30, then that person probably has a problem — fatty liver or some vascular disease, including occlusive coronary artery disease.”

AASLD 57th Annual Meeting: Abstract 95, presented October 30, 2006; abstract 1251, presented October 31, 2006.

Alanine Aminotransferase (ALT) | HealthLink BC

Test Overview

An alanine aminotransferase (ALT) test measures the amount of this enzyme in the blood. ALT is found mainly in the liver, but also in smaller amounts in the kidneys, heart, muscles, and pancreas. ALT was formerly called serum glutamic pyruvic transaminase (SGPT).

ALT is measured to see if the liver is damaged or diseased. Low levels of ALT are normally found in the blood. But when the liver is damaged or diseased, it releases ALT into the bloodstream, which makes ALT levels go up. Most increases in ALT levels are caused by liver damage.

The ALT test is often done along with other tests that check for liver damage, including aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin. Both ALT and AST levels are reliable tests for liver damage.

Why It Is Done

The alanine aminotransferase (ALT) test is done to:

• Identify liver disease, especially cirrhosis and hepatitis caused by alcohol, drugs, or viruses.
• Help check for liver damage.
• Find out whether jaundice was caused by a blood disorder or liver disease.
• Keep track of the effects of cholesterol-lowering medicines and other medicines that can damage the liver.

How To Prepare

Avoid strenuous exercise just before having an ALT test.

Tell your doctor:

Talk to your doctor about any concerns you have regarding the need for the test, its risks, how it will be done, or what the results may mean. To help you understand the importance of this test, fill out the medical test information form .

How It Is Done

The health professional taking a sample of your blood will:

• Wrap an elastic band around your upper arm to stop the flow of blood. This makes the veins below the band larger so it is easier to put a needle into the vein.
• Clean the needle site with alcohol.
• Put the needle into the vein. More than one needle stick may be needed.
• Attach a tube to the needle to fill it with blood.
• Remove the band from your arm when enough blood is collected.
• Put a gauze pad or cotton ball over the needle site as the needle is removed.
• Put pressure on the site and then put on a bandage.

How It Feels

The blood sample is taken from a vein in your arm. An elastic band is wrapped around your upper arm. It may feel tight. You may feel nothing at all from the needle, or you may feel a quick sting or pinch.

Risks

There is very little chance of a problem from having blood sample taken from a vein.

• You may get a small bruise at the site. You can lower the chance of bruising by keeping pressure on the site for several minutes.
• In rare cases, the vein may become swollen after the blood sample is taken. This problem is called phlebitis. A warm compress can be used several times a day to treat this.

Results

An alanine aminotransferase (ALT) test measures the amount of this enzyme in the blood. Results are usually available within 12 hours.

Normal

The normal values listed here—called a reference range—are just a guide. These ranges vary from lab to lab, and your lab may have a different range for what’s normal. Your lab report should contain the range your lab uses. Also, your doctor will evaluate your results based on your health and other factors. This means that a value that falls outside the normal values listed here may still be normal for you or your lab.

High values

High levels of ALT may be caused by:

• Liver damage from conditions such as hepatitis or cirrhosis.
• Lead poisoning.
• Very strenuous exercise or severe injury to a muscle.
• Exposure to carbon tetrachloride.
• Decay of a large tumour (necrosis).
• Many medicines, such as statins, antibiotics, chemotherapy, aspirin, opioids, and barbiturates.
• Mononucleosis.
• Growth spurts, especially in young children. Rapid growth can cause mildly elevated levels of ALT.

What Affects the Test

You may not be able to have the test, or the results may not be helpful, if:

• You take some natural health products, such as echinacea and valerian.
• You recently had cardiac catheterization or surgery.

What To Think About

• The alanine aminotransferase (ALT) value is often used along with the results of the aspartate aminotransferase (AST) test to obtain the AST to ALT ratio. This value can often help determine whether there is damage to the liver related to heavy alcohol use. For more information, see the topic Aspartate Aminotransferase (AST).
• The gamma glutamyl transferase (GGT) test is sometimes done along with other liver enzyme tests.
• In children with acute lymphocytic leukemia (ALL), very high ALT levels may mean that the disease is likely to progress rapidly.
• Many different conditions can raise ALT blood levels, so other testing is usually needed to interpret an abnormal ALT result.

References

Citations

1. Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.

Other Works Consulted

• Chernecky CC, Berger BJ (2013). Laboratory Tests and Diagnostic Procedures, 6th ed. St. Louis: Saunders.
• Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.
• Pagana KD, Pagana TJ (2010). Mosby’s Manual of Diagnostic and Laboratory Tests, 4th ed. St. Louis: Mosby.

Credits

Current as of:
December 9, 2019

Author: Healthwise Staff
Medical Review:
E. Gregory Thompson MD – Internal Medicine
Anne C. Poinier MD – Internal Medicine
Adam Husney MD – Family Medicine
Martin J. Gabica MD – Family Medicine
Kathleen Romito MD – Family Medicine
Jerome B. Simon MD, FRCPC, FACP – Gastroenterology

Current as of: December 9, 2019

Author: Healthwise Staff

Medical Review:E. Gregory Thompson MD – Internal Medicine & Anne C. Poinier MD – Internal Medicine & Adam Husney MD – Family Medicine & Martin J. Gabica MD – Family Medicine & Kathleen Romito MD – Family Medicine & Jerome B. Simon MD, FRCPC, FACP – Gastroenterology

Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.

Liver Function Blood Tests Explained

Liver Blood Tests Explained

Blood tests and Investigations for Liver Function              

Some of the standard or routine blood tests that your doctor will order to check “liver function” are in reality only able to detect liver damage. These tests may not be sensitive enough to accurately reflect whether your liver is functioning at its optimum level. These tests will usually be abnormal in significant liver disease or liver distress; however, they can still give normal readings in some cases of mild liver disease.  

Healthy ranges for Blood tests for Liver Function

ALT 0 – 45 U/L

GGT 0 – 45 U/L

AST 0 – 45 U/L

ALP 30 – 120 U/L

BILIRUBIN 0 – 20 U/L or 0.174 to 1.04 mg/dL

ALBUMIN 38 – 55 g/L or 3.8 to 5.5g/dL 

AFP 20 – 32 g/L or 2 to 3.2g/dL

ALT
(alanine aminotransferase), sometimes called SPGT just to confuse us,  is elevated showing inflammation of the liver.

Our ALT shows up high whenever our liver is dealing with any infection or poison or even a hard to digest food such as fried meat. It is common for them to be high in people who have recently had alcohol or paracetamol. With infections, and these can be other diseases like flu or an septic wound they go up as the liver fights back. If they are constantly in the 50 to 200 range we term the hepatitis B infection active. ALT’s range from 0 up to 3000 or so in many acute hepatitis cases. They change with every meal so it is important not to panic if they go from 20 to 45 after a few months. All scores below 45 indicate a perfectly healthy score.

GGT
(gamma glutamyl transpeptidase) is elevated in those who use alcohol or toxins.

Our GST shows up high between 50 and 200 if we are often taking paracetamol or using alcohol a lot. It is often a sign of alcoholism or longer term liver damage, but can be reversed by adopting a alcohol free or toxin free lifestyle.

BILIRUBIN 

If our Bilirubin is elevated, the patient may have a yellow colour skin and eyes, jaundice. Bilirubin is a bile product made by the liver to digest food and it often is overproduced when we first get Hepatitis B or C, then it back fires into the blood stream causing the yellow effect to eyes and skin. It can cause itching and skin irritation as it is sweated out. If it goes up during chronic Hepatitis B or C infection it is a sign of poor food and drink or liver disease. Milk thistle herbal pills are proven to help lower Bilirubin scores so many Hepatitis patients take it.

AFP
(Alpha Feta Globulin Protein). If our AFP is elevated it usually mean excessive inflammation in the liver and/or immune system. Very high levels may be seen in some types of cancers. It is important the many women diagnosed during pregnancy remember it goes up sometimes because of Pregnancy, a score of 40 g/l is not a sign of liver cancer, scores that may indicate a cancer tend to be in the hundreds

AST
(aspartate aminotransferase) also called SGOT, is elevated in heart, muscle and liver diseases.

ALP
(alkaline phosphatase) is elevated in many types of liver and non liver disease.

ALBUMIN
falling levels of blood albumin show deteriorating liver function.

Up to 80% of Hepatitis B and C patients usually have normal, perfectly healthy scores for liver function, these are termed inactive or healthy patients.

Viral Hepatitis Liver Tests – the 4 main Results and Stages

Viral Hepatitis Patients tend to present with 4 types of LFT Result, 3 factors most affect the liver results 

Viral Load, Time Infected and Toxins

Stage 1 – All Normal 

Means hepatitis is having little effect and you are best monitored yearly for activity

Stage 2 – ALT is persistently above 50
but your LFT’s are Normal

Means you have an active hepatitis infection which over decades can cause 

Fibrosis without additional toxins like alcohol or being overweight and is best treated at some point and slowed with a liver friendly diet

Your Liver Team should provide a Personalised Care Plan if

Stage 3 – ALT/AST/GGT are 50 to 200 

Usually means you have taken liver toxins that worsen viral hepatitis eg alcohol, barbiturates, 

benzodiazepines, anticonvulsants, warfarin, antidepressants, paracetamol, 

or you may also have fatty liver from obesity

Stage 4 – GGT /ALT are 50 to 200 and ALP is above 200

Liver cells are damaged Cirrhosis and Fibrosis have occurred, liver functions 

can fall, tumours can occur. The author of this site was diagnosed in this stage 12 years ago,

point being a liver friendly diet, treatment and he is fine now.

Got Elevated Liver Enzymes? – Here’s How To Interpret Your Liver Function Tests

 

Both exercise, supplements, medications and drugs may cause blood elevations of enzymes that are commonly included in liver function and/or liver disease testing – alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).[1-6]

 

Elevations in these enzymes are one of the most common “problems” encountered in everyday clinical practice.[7] 

 

But how does one distinguish pathological elevations vs. those caused by intense exercise?

 

Liver Function Testing – basics

 

5 blood tests – ALT, AST ALP, GGT (gammaglutamyltransferase) and bilirubin – are included in liver function tests.[8] ALT, AST and ALP are also included in the Comprehensive Metabolic Panel (CMP), which is part of common routine blood work.

 

ALT and AST are also known as aminotransferases or transaminases. They are considered good markers of liver inflammation that may impair its function.[9] ALT is regarded as a reliable marker of liver damage or liver disease, as well as an indicator of overall health.[7, 10-12]

 

The name “liver function testing” is, however, somewhat of a misnomer; these tests are neither specific to the liver – the enzymes are also present in other tissues, e.g. AST is present in a far greater amounts in muscle than the liver – nor true measures of liver function. Rather than assessing functions of the liver, the release of ALT and ALP (and AST to a much lesser extent) from liver cells to the bloodstream indicates liver cell damage or death, and/or blockage or damage in the biliary system (a.k.a. cholestasis), if ALP and bilirubin are elevated).[13] Thus, the term “liver injury tests” would be more appropriate.[14]

 

True indicators of liver function are tests that directly or indirectly measure substances synthesized or metabolized by the liver, and include albumin (which is part of the CMP panel), prothrombin time (reflecting clotting factors produced by the liver) and bilirubin.[8, 15]

 

How high elevations in ALT and AST are accepted?

 

Even though there is no universal agreement on what constitutes mild, moderate or marked aminotransferase elevation, a general clinical practice guideline is: [7]

 

– Mild elevation = less than 5 times the upper reference limit.

– Moderate elevation = 5–10 times the upper reference limit.

– Marked elevation = over 10 times the upper reference limit.

 

Now, let’s compare this to commonly encountered elevations in aminotransferases – and other labs – caused by intense exercise…

 

How does exercise impact common blood tests?

 

Weightlifting results in profound increases in liver related parameters; these elevations can be prolonged, lasting for 1 week after performing an intense weightlifting workout.[16] Table 1 summarizes blood tests that are commonly used to assess liver function. Note that the normal range values may vary slightly from laboratory to laboratory. They also can vary with age and gender.

 

Table 1: Non-pathological elevations of common blood tests after strenuous exercise in healthy people.  

Data compiled from references [16-19].

 

* The numbers indicate fold-elevation above the upper end of the normal range, caused by intense exercise, in healthy people.

 

IU/L = International units per liter

ALT = alanine aminotransferase

ALP = alkaline phosphatase

AST = aspartate aminotransferase

 

Elevations in these enzymes are proportional to body weight, exercise type (resistance exercise in general increasing levels more than aerobic exercise), and exercise intensity.[17] Anabolic steroid–using bodybuilders have the highest enzyme levels, but the steroid-free bodybuilders and exercising male students also have significantly elevated levels of AST and CK.[17]

 

For drug-induced liver injury, the ALT cut off point of 5-fold over the upper end of the normal range (or 3-fold if total bilirubin exceeds its normal range by 2-fold).[20] As indicated in the table, intense exercise may rise ALT 5-fold. The question becomes, how does one know if enzyme elevations are a harmless response to exercise, or an indication of liver damage?

 

How to distinguish exercise-induced elevations in transaminases from those caused by liver disease?

 

The simplest blood test that should be included when examining liver health in people engaging in regular intense resistance exercise is GGT (gamma-glutamyltranspeptidase). The reason is that GGT distinguishes healthy people with resistance training induced elevations in ALT and AST from patients with hepatitis.[17] One notable study found that bodybuilders (both anabolic steroid non-users and users) both had a GGT level around 30 U/L (normal range for this assay; 8-78 U/L), while hepatitis patients had GGT levels of 212 U/L (i.e. a 2.7-fold elevation above the upper end of normal range).[17] This was confirmed in another study which showed that resistance exercise can cause highly pathological liver function tests in healthy men; while ALT, AST and CK were greatly elevated, GGT was not.[16] Thus, including GGT in blood testing for evaluation of liver status will help differentiation between transaminase elevations due to muscle damage vs. liver damage. While GGT is a simple parameter to measure, it is not included in routine clinical lab panels, and thus has to be specifically requested.

 

---

Side note:

 

Bilirubin – which is also included in the CMP panel – can support a diagnosis of drug-induced liver injury, which often presents with elevated bilirubin levels, often combined with elevated ALP levels and an ALT/ALP ratio below 2.[21]

 

---

Do typical doctors know this?

 

Short answer; most don’t!

 

Many doctors, even gastroenterologists or internists, don’t know that intense exercise can cause highly pathological liver function/disease lab tests, and they often refer a perfectly healthy person who happens to be exercising – whose lifestyle history has not been taken – to a liver disease specialist.[9]

 

An interesting survey assessed whether primary care physicians accurately can distinguish between blood aminotransferase elevations caused by intense resistance training and indicating muscle damage vs. elevation caused by drug use.[18] Surveys were sent to physicians listed as practicing family medicine or sports medicine in the yellow pages of seven metropolitan areas. Blood test results showed elevated aspartate AST, ALT and CK, but normal GGT. It was found that 56% failed to mention muscle damage as a potential diagnosis, despite the markedly elevated CK level of the patient. 63% indicated liver disease as their primary diagnosis despite normal GGT levels.[18]

 

Importance of clinical context when interpreting enzyme elevations

 

While intense exercise increases ALT and AST in healthy people, in sedentary patients with chronic liver disease – including NASH (nonalcoholic steatohepatitis) – modest physical activity reduces elevated ALT levels caused by the liver disease.[22, 23] In addition, the blood ALT levels in people who exercise at customary levels are lower than in untrained people undertaking the same exercise, and exercising more strenuously than customary may elevate ALT levels.[7]

 

It should be noted that markers of liver function/disease are also associated with cardiovascular disease.[6, 12, 24] Many studies have linked liver function/disease markers – ALT and GGT levels in particular – to later development of the metabolic syndrome, diabetes, high blood pressure, cholesterol abnormalities and heart disease [25-30], as well as cancer [31] and all-cause mortality.[32]

 

Therefore, it is critical to look at the complete picture when interpreting liver related labs. A fit regularly exercising person who is not taking any drugs may have ALT and AST levels in the same range as a patient with hepatitis or an alcoholic. This does not mean that the exerciser’s liver is in danger or that he/she will develop cardiovascular disease.

 

Summary

 

Interpreting the liver function/disease test results requires taking into account the whole clinical picture, as a healthy person who trains hard can have elevations in some labs to the same degree that is seen in patients with liver disease. In this scenario, these elevations do not indicate liver dysfunction, nor impending metabolic syndrome or cardiovascular disease.

 

When in doubt, make sure your doctor checks your GGT level together with the transaminases (ALT and AST) and ALP that you get from the standard Comprehensive Metabolic Panel. Because GGT is not included in routine clinical lab panels, you have to specifically request it.

 

 

References:

 

1.            Bhardwaj, S.S. and N. Chalasani, Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis, 2007. 11(3): p. 597-613, vii.

2.            Teschke, R. and A. Eickhoff, Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps. Front Pharmacol, 2015. 6: p. 72.

3.            McKenney, J.M., et al., A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA, 1994. 271(9): p. 672-7.

4.            Guyton, J.R. and H.E. Bays, Safety considerations with niacin therapy. Am J Cardiol, 2007. 99(6A): p. 22C-31C.

5.            Rizakallah, G.S., et al., Clinical inquiries. Should liver enzymes be checked in a patient taking niacin? J Fam Pract, 2005. 54(3): p. 265-8.

6.            Hall, P. and J. Cash, What is the real function of the liver ‘function’ tests? Ulster Med J, 2012. 81(1): p. 30-6.

7.            Giannini, E.G., R. Testa, and V. Savarino, Liver enzyme alteration: a guide for clinicians. CMAJ, 2005. 172(3): p. 367-79.

8.            Titcomb, C.P., Jr., Liver function tests: what is the risk? J Insur Med, 2003. 35(1): p. 26-35.

9.            Transaminase levels and vigorous exercise. Gastroenterol Hepatol (N Y), 2007. 3(12): p. 913-4.

10.          Kim, W.R., et al., Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology, 2008. 47(4): p. 1363-70.

11.          Sherman, K.E., Alanine aminotransferase in clinical practice. A review. Arch Intern Med, 1991. 151(2): p. 260-5.

12.          Liu, Z., et al., Alanine aminotransferase-old biomarker and new concept: a review. Int J Med Sci, 2014. 11(9): p. 925-35.

13.          Botros, M. and K.A. Sikaris, The de ritis ratio: the test of time. Clin Biochem Rev, 2013. 34(3): p. 117-30.

14.          Thapa, B.R. and A. Walia, Liver function tests and their interpretation. Indian J Pediatr, 2007. 74(7): p. 663-71.

15.          Smellie, W.S., et al., Best practice in primary care pathology: review 5. J Clin Pathol, 2006. 59(12): p. 1229-37.

16.          Pettersson, J., et al., Muscular exercise can cause highly pathological liver function tests in healthy men. Br J Clin Pharmacol, 2008. 65(2): p. 253-9.

17.          Dickerman, R.D., et al., Anabolic steroid-induced hepatotoxicity: is it overstated? Clin J Sport Med, 1999. 9(1): p. 34-9.

18.          Pertusi, R., R.D. Dickerman, and W.J. McConathy, Evaluation of aminotransferase elevations in a bodybuilder using anabolic steroids: hepatitis or rhabdomyolysis? J Am Osteopath Assoc, 2001. 101(7): p. 391-4.

19.          Chen, T.C. and S.S. Hsieh, Effects of a 7-day eccentric training period on muscle damage and inflammation. Med Sci Sports Exerc, 2001. 33(10): p. 1732-8.

20.          Aithal, G.P., et al., Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther, 2011. 89(6): p. 806-15.

21.          Velayudham, L.S. and G.C. Farrell, Drug-induced cholestasis. Expert Opin Drug Saf, 2003. 2(3): p. 287-304.

22.          Sreenivasa Baba, C., et al., Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis. J Gastroenterol Hepatol, 2006. 21(1 Pt 1): p. 191-8.

23.          Whitsett, M. and L.B. VanWagner, Physical activity as a treatment of non-alcoholic fatty liver disease: A systematic review. World J Hepatol, 2015. 7(16): p. 2041-52.

24.          Targher, G. and C.D. Byrne, Circulating Markers of Liver Function and Cardiovascular Disease Risk. Arterioscler Thromb Vasc Biol, 2015.

25.          Ioannou, G.N., et al., Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology, 2006. 43(5): p. 1145-51.

26.          Fraser, A., et al., Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women’s Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol, 2007. 27(12): p. 2729-35.

27.          Liu, X., et al., Circulating alanine transaminase (ALT) and gamma-glutamyl transferase (GGT), but not fetuin-A, are associated with metabolic risk factors, at baseline and at two-year follow-up: the prospective Cyprus Metabolism Study. Metabolism, 2014. 63(6): p. 773-82.

28.          Kunutsor, S.K., T.A. Apekey, and H. Khan, Liver enzymes and risk of cardiovascular disease in the general population: a meta-analysis of prospective cohort studies. Atherosclerosis, 2014. 236(1): p. 7-17.

29.          Kunutsor, S.K., et al., Serum Alkaline Phosphatase and Risk of Incident Cardiovascular Disease: Interrelationship with High Sensitivity C-Reactive Protein. PLoS One, 2015. 10(7): p. e0132822.

30.          Lee, D.S., et al., Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol, 2007. 27(1): p. 127-33.

31.          Kunutsor, S.K., et al., Gamma glutamyltransferase, alanine aminotransferase and risk of cancer: systematic review and meta-analysis. Int J Cancer, 2015. 136(5): p. 1162-70.

32.          Kunutsor, S.K., et al., Liver enzymes and risk of all-cause mortality in general populations: a systematic review and meta-analysis. Int J Epidemiol, 2014. 43(1): p. 187-201.

 

 

Alanine aminotransferase (ALT) – Lab Tests Online AU

How is it used?

When is it requested?

A doctor usually requests an ALT test with other laboratory investigations to evaluate a patient who has of a liver disorder. Some of these symptoms include , dark urine, nausea, vomiting, abdominal swelling, unusual weight gain and abdominal pain. ALT can also be used, either by itself or with other tests, for:

• persons who have a history of known or possible exposure to hepatitis
• those who drink too much alcohol,
• those whose family have a history of liver disease,
• people who take drugs that might damage the liver.

In people with mild symptoms, such as tiredness or loss of energy, ALT may be tested to make sure they do not have chronic (long-term) liver disease. ALT is often used to monitor the treatment of persons who have liver disease, to see if the treatment is working, and may be ordered either by itself or along with other tests.

What does the test result mean?

Very high levels of ALT (more than 10 times the highest normal level) are usually due to (short-term) hepatitis, often due to a . In acute hepatitis, ALT levels usually stay high for about 1–2 months, but can take as long as 3–6 months to return to normal.

ALT levels are usually not as high in hepatitis, often less than 4 times the highest normal level: in this case, ALT levels often vary between normal and slightly increased, so doctors will order the test frequently to see if there is a pattern. In some liver diseases, especially when the ducts are blocked, or when a person has , ALT may be close to normal levels.

Reference Intervals

Adult

Male         5 – 40 U/L
Female     5 – 35 U/L

The reference intervals shown above are known as a harmonised reference interval. This means that eventually all laboratories in Australia will eventually use this same interval so wherever your sample is tested, the reference interval should be the one shown above. Laboratories are in the process of adopting these harmonised intervals so it is possible that the intervals shown on the report of your results for this test may be slightly different until this change is fully adopted. More information can be found under Reference Intervals – An Overview.

Is there anything else I should know?

Certain drugs may raise ALT levels by causing liver damage in a very small percentage of patients taking the drug. This is true of both prescription drugs and some ‘natural’ health products. If your doctor finds that you have a high ALT, tell him or her about all the drugs and health products you are taking.

Alanine Aminotransferase Decreases with Age: The Rancho Bernardo Study

Abstract

Background

Serum alanine aminotransferase (ALT) is a marker of liver injury. The 2005 American Gastroenterology Association Future Trends Committee report states that serum ALT levels remain constant with age. This study examines the association between serum ALT and age in a community-dwelling cohort in the United States.

Methods

A cross-sectional study of 2,364 (54% female) participants aged 30–93 years from the Rancho Bernardo Study cohort who attended a research clinic visit in 1984–87. Demographic, metabolic co-variates, ALT, bilirubin, gamma glutamyl transferase (GGT), albumin, and adiposity signaling biomarkers (leptin, IL-6, adiponectin, ghrelin) were measured. Participants were divided into four-groups based upon age quartile, and multivariable-adjusted least squares of means (LSM) were examined (p for trend <0.05).

Results

ALT decreased with increasing age, with mean ALT levels (IU/L) of 23, 21, 20, and 17 for those between quartile ages 30–62, 63–71, 72–77, and 78–93 years (p<0.0001). Trends of decreasing LSM ALT with age and the decreasing prevalence of categorically defined elevated serum ALT with age remained robust after adjusting for sex, alcohol use, metabolic syndrome components, and biomarkers of adiposity (p-value <0.0001), and was not materially changed after adjusting for bilirubin, GGT, and albumin.

Conclusions

ALT levels decrease with age in both men and women independent of metabolic syndrome components, adiposity signaling biomarkers, and other commonly used liver function tests. Further studies are needed to understand the mechanisms responsible for a decline in ALT with age, and to establish the optimal cut-point of normal ALT in the elderly.

Citation: Dong MH, Bettencourt R, Barrett-Connor E, Loomba R (2010) Alanine Aminotransferase Decreases with Age: The Rancho Bernardo Study. PLoS ONE 5(12):
e14254.

https://doi.org/10.1371/journal.pone.0014254

Editor: Man-Fung Yuen, The University of Hong Kong, Hong Kong

Received: July 7, 2010; Accepted: November 9, 2010; Published: December 8, 2010

Copyright: © 2010 Dong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work is supported in part by the American Gastroenterological Association (AGA) Foundation – Sucampo – ASP Designated Research Award in Geriatric Gastroenterology and by a T. Franklin Williams Scholarship Award; Funding was provided by Atlantic Philanthropies, Inc, the John A. Hartford Foundation, the Association of Specialty Professors, and the American Gastroenterological Association to Rohit Loomba, MD, MHSc. This research was funded in part with the support of the UCSD Digestive Diseases Research Development Center, U.S. PHS grant #DK080506. This work was supported in part by the National Institutes of Health grants RO1AG28507, R37AG007181, and RO1DK31801 to Elizabeth Barrett-Connor, MD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Serum alanine aminotransferase (ALT) level is frequently used as a surrogate marker for hepatocyte injury. Normal ranges vary according to the commercial kit used, but have historically been set at around 40 IU/L. This value was based on population studies conducted before the availability of blood tests for hepatitis C and before the widespread recognition of nonalcoholic fatty liver disease (NAFLD). Recently, some have suggested that not only should the upper limits of normal for ALT be lowered, but that limits should differ based on sex as well [1], [2], [3]. Since then, many other factors have been implicated in differing ALT levels. Most of these factors are features related to the metabolic syndrome, including body mass index, waist-hip ratio, dyslipidemia, and glucose intolerance [4]–[13]. The relationship between ALT and age, however, remains somewhat ambiguous.

The 2005 American Gastroenterology Association Future Trends Committee report regarding the effects of aging on future trends in gastroenterology states that there is no effect of age on conventional liver function tests, including serum ALT [14]. A study of serum ALT concentrations in healthy Iranian blood donors also concluded that ALT did not correlate with age [15]. However, a few studies published since that time have reported that the prevalence of elevated (abnormal) ALT decreases with age [4], [6], [7], [8], [10], [11]. Some have found this association to be true in men, but not in women [3], [5], [16]. Most of these studies were performed using retrospective chart reviews of patients who had laboratory tests, including serum ALT, for medical reasons, in self-selected populations (such as blood donors), or in Asian populations, whose liver function may differ compared to Western populations. A recent study of community dwelling elderly men (over age 70) suggested that ALT may be a novel biomarker of aging, with levels decreasing with rising age, and low levels associating with frailty and reduced survival [17].

The largest United States population-based study of ALT levels is from the National Health and Nutrition Examination Survey (NHANES). In both the 1988–1994 [6] (elevated ALT defined as >40 U/L in men and >31 U/L in women) and the 1999–2002 [7] (elevated ALT defined as >43 U/L in both men and women) cross-sectional reports, older age was associated with a decreased prevalence of elevated ALT levels, but the conventionally higher ALT cutoff values were used in these analyses. It is therefore uncertain whether age was associated with serum ALT concentrations within the normal range, and whether the associations between age and the prevalence of categorically defined elevated ALT would have remained had lower ALT thresholds been applied. The latter question was answered by Ruhl and Everhart [4], who examined data from the NHANES 1988–1994 survey using both the traditionally higher ALT cutoff threshold (>43 IU/L) as well as lower thresholds (≥30 IU/L for men and ≥19 IU/L for women). They found that in univariate analysis, younger age was associated with abnormally elevated ALT activity.

Thus, there seems to be an association between younger age and increased prevalence of elevated ALT. However, it is still unclear whether serum ALT levels within the normal range decline with age, and if so, whether this decline is related to changes in body mass, central adiposity, or other plausible covariates. Additionally, it is unclear whether the threshold of extreme values of ALT (e.g. 95^th percentile of ALT range for a particular age group) also varies with age.

To the best of our knowledge, this paper is the first to examine the association between serum ALT level as a continuous variable and age, including ALT levels that are within normal range as well as those that are elevated, in a well-characterized [12], [18], [19], healthy, community-dwelling cohort of older men and women residing in Southern California. We also determined whether any age-related changes in serum ALT were explained by metabolic syndrome components, adiposity-related biomarkers including leptin, adiponectin, ghrelin and interleukin-6 (IL-6), or other markers of hepatic function (bilirubin, albumin, gamma glutamyl transferase [GGT]).

Methods

Study Cohort and Setting

This cross-sectional study is based on data from participants of the Rancho Bernardo Study (RBS). The RBS cohort was established in 1972, when 82% of residents of a geographically defined suburban Southern California community were recruited to a study of heart disease risk factors. The details of the cohort, selection criteria, and purpose of the RBS have been published elsewhere [18], [19]. The current study cohort was derived from 2480 residents who attended the research clinic between 1984 and 1987, approximately 80% of the surviving, local, community-dwelling adults. Of these, 2364 participants were aged 30 years or older and had available ALT data and were included in the current analysis [12]. The RBS cohort is almost entirely Caucasian of European ancestry, most with at least some college education, and largely white-collar workers. All participants gave written informed consent; the study was approved by the institutional review board of the University of California, San Diego.

Clinical and Laboratory Assessment

A trained interviewer gathered information regarding medical history and current medication use. Weight was obtained with participants wearing light clothing and no shoes. Height, waist and hip circumference, and systolic blood pressure were obtained in clinic by trained investigators. Blood pressure was obtained from two morning readings with the resting participant in the seated position, using a regularly calibrated mercury sphygmomanometer, according to the Hypertension Detection and Follow-up Program protocol [20]. Alcohol use, in terms of amount, type, and frequency, was self-reported. One alcoholic drink was defined as 10 g of alcohol. Alcohol use was indirectly validated by showing a similar quantitative response to a nutritionist interviewer who obtained alcohol intake as part of a separate food-frequency questionnaire. Fasting venous blood was analyzed in a clinical laboratory. ALT, bilirubin, GGT and albumin were measured using a single assay by spectrophotometry on fresh samples. Fasting serum samples were obtained during the research visit; they were measured in all participants using the same assay and under identical testing conditions at a UCSD clinical laboratory. Total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were measured using enzymatic methods in a Lipid Research Clinic-certified laboratory. Plasma glucose was measured in a hospital laboratory using the glucose-oxidase method. Diabetes was defined as a fasting glucose of ≥126 mg/dL (≥7 mmol/L) or treatment with either insulin or an oral hypoglycemic medication. Adipocytokine studies were performed on samples stored at −70°C. IL6 was measured using an enzyme-linked immunosorption assay (Quantikine HS, R&D Systems, Minneapolis, MN) on previously unthawed samples in 2000. Adiponectin, ghrelin, and leptin were measured in 2004 (samples thawed for a second time) by radioimmunoassay (Linco Diagnostics Laboratory, St. Louis, MO) as previously reported [21], [22]. The laboratory reports that there is no loss of assay sensitivity or adipocytokine degradation with two freeze-thaw cycles, and levels in our study are similar to those reported in the literature using the same assays [23], [24], [25], [26]. Adequate blood samples for serum leptin, IL-6, adiponectin, and ghrelin concentrations were available for 1565, 1843, 1572, and 1556 of 2364 individuals, respectively.

Elevated ALT was defined, a priori, as an ALT ≥30 IU/L for men and ≥19 IU/L for women as proposed by Prati et al [2].

Statistical Analysis

The cohort was divided into the following four groups based upon the age quartiles: 30–62, 63–71, 72–77, and 78–93 years. Descriptive statistics were described in participants classified into these quartile age groups. Serum ALT, bilirubin, GGT, albumin, triglycerides, IL-6, leptin, adiponectin, and ghrelin were log transformed for statistical analyses to fulfill conditions of normality. Least squares means were used to examine the trends in serum ALT, bilirubin, GGT, and albumin across the four age groups and p-value for trend was examined. Multivariate hierarchical models were used to examine the relationship between ALT and age that included: 1. Un-adjusted, 2. Multiply adjusted for sex, BMI, systolic blood pressure, alcohol use, waist-hip ratio, diabetes, fasting glucose, total cholesterol-HDL cholestrol ratio, triglycerides, IL-6, leptin, adiponectin, and ghrelin, and 3. Multiply adjusted with the above plus commonly used liver function tests (bilirubin, GGT, and albumin). Additionally, we conducted multivariate-adjusted models to examine the association between age and prevalence of categorically defined elevated serum ALT across these four age groups, and p-value for trend was examined. Statistical analyses were conducted using SAS version 9.2 (SAS Institute, Cary, NC). A two-tailed p-value of less than 0.05 was considered statistically significant.

Results

Population Characteristics

Cohort characteristics of the 1044 men (44.2%) and 1320 women (55.8%) are shown in table 1. The mean ± standard deviation (SD) age was 69.6±10.5 years, range 30–93 years. Average (mean ± SD) BMI was 24.9±3.7 kg/m² and average waist-hip ratio was 0.8±0.1. 36.8% reported no alcohol use, 22% reported <1 drink/day, 26.8% reported 1–2 drinks/day, and 14.5% reported >2 drinks/day. The mean ± SD systolic blood pressure was 139±22 mmHg. The mean ± SD for total and HDL cholesterol was 220±40 mg/dL and 62±19 mg/dL, respectively. 14.3% of the cohort had diabetes. Geometric mean (95% CI) concentrations for leptin, IL-6, adiponectin, and ghrelin were 8.6 µg/L (8.2–8.9 µg/L), 2.4 pg/ml (2.3–2.5pg/ml), 11.7 µg/ml (11.3–12.0 µg/ml), and 1345.3 pg/ml (1317.9–1373.2 pg/ml), respectively. Geometric means (95% CI) for bilirubin, GGT, and albumin were 0.5 mg/dl (0.5–0.5 mg/dl), 9.8 IU/L (9.5–10.1 IU/L), and 4.3 g/dl (4.3–4.3 g/dl), respectively.

Analysis of each of these variables by age showed a significant age trend for BMI, waist-hip ratio (marker of central adiposity), alcohol use, systolic blood pressure, elevated cholesterol, prevalence of diabetes, leptin, adiponectin, IL-6, bilirubin, and albumin with increasing age. BMI and albumin decreased with increasing age, while waist-hip ratio, systolic blood pressure, prevalence of diabetes, adiponectin, IL-6, and bilirubin increased with age. GGT did not show a significant trend with age.

ALT Trends

Serum ALT Declines With Age.

For all participants combined, ALT was highest in the youngest (30–62) age group, with a mean ± SD ALT of 23±15 IU/L for that group. Subsequently, ALT decreased with increasing age, from 21±14 IU/L for those aged 63–71 years, to 20±21 IU/L for those aged 72–77 years, and 17±10 IU/L for those aged 78–93 years.

In sex-specific analyses, ALT decreased with increasing age for both men and women. In men, the highest ALT of 26.5±14.9 IU/L was observed in the 30–62 year age group, subsequently dropping to 22.7±15.6 IU/L, 21.4±30.5 IU/L, and 17.9±9.1 IU/L for each of the progressive age subcategories (Figure 1). ALT in women started at 20.1±14.0 IU/L in the 30–62 year age group, then gradually dropped thereafter to 19.5±11.8 IU/L, 18.6±10.2 IU/L, and 16.8±11.1 IU/L for the subsequent age subcategories (Figure 2). The 95th percentile cutoff value for ALT also decreased with age, suggesting that extreme ALT values for each respective age-category declined as well (Figures 1 and 2).

Least Squares of Mean of ALT and Age.

Results remained consistent when least squares means of serum ALT were analyzed across all four age groups, using p-value for trend (p-value <0.0001). After multivariable adjustment for sex, BMI, systolic blood pressure, alcohol use, waist-hip ratio, diabetes, fasting glucose, total cholesterol to HDL radio, triglycerides, IL-6, adiponectin, and ghrelin, the trend of decreasing least squares means of ALT with age remained consistent and statistically significant (p<0.0001). Addition of bilirubin, GGT, and albumin to the multivariable model did not significantly change the statistical association (p<0.0001) (Table 2).

Elevated ALT Declines With Age.

Using elevated ALT cutoff values of ≥30 IU/L for men and ≥19 IU/L for women as proposed by Prati et al. [2], the prevalence of abnormally elevated ALT was highest in the 30–63 year age group at 35.3%, then subsequently gradually declined to 31%, 28.4%, and 17.4% for each progressive age subcategory (p<0.0001) (Figure 3).

Figure 3. Prevalence of Elevated ALT by Age.

The trend of decreasing prevalence of elevated ALT with rising age persists in unadjusted analysis, after adjustment for sex, BMI, systolic blood pressure, alcohol use, waist-hip ratio, diabetes, fasting glucose, total-HDL ratio, triglycerides, adiposity biomarkers (leptin, adiponectin, ghrelin, IL-6), and after adjustments for the above plus bilirubin, GGT, and albumin.

https://doi.org/10.1371/journal.pone.0014254.g003

Similarly, after multivariate adjustment of prevalence of elevated ALT for sex, BMI, systolic blood pressure, alcohol use, waist-hip ratio, diabetes, fasting glucose, total cholesterol to HDL ratio, triglycerides, leptin, IL-6, adiponectin, ghrelin, bilirubin, GGT, and albumin, results remained statistically significant and showed a consistent downward trend of prevalence of elevated ALT with increasing age (p = 0.0001, Figure 3).

Trends in Bilirubin, GGT, and Albumin

In unadjusted analyses, rising bilirubin (from 0.4 mg/dL in the youngest quartile to 0.6 mg/dL in the oldest quartile) and falling albumin (from 4.4 g/dL in the youngest quartile to 4.1 g/dL in the oldest quartile) were associated with increasing age, while GGT had no association. After multivariable adjustments for sex, BMI, systolic blood pressure, alcohol use, waist-hip ratio, diabetes, fasting glucose, total-HDL ratio, triglycerides, and adiposity biomarkers (leptin, adiponectin, ghrelin, IL-6), trends in rising bilirubin and falling GGT and albumin levels with increasing age remained significant with p-values for trend <0.05. Bilirubin increased from 0.4 mg/dL in the youngest group to 0.6 mg/dL in the oldest group, GGT decreased from 11.7 IU/L in the youngest group to 9.9 IU/L in the oldest group, and albumin decreased from 4.5 g/dL to 4.2 g/dL in those groups.

Discussion

Principal Findings

In this population-based, community-dwelling cohort of older men and women residing in Southern California, ALT levels decreased with age for both sexes. Even after multivariate adjustments for factors previously found in other studies to be associated with differing ALT levels (sex [2], [4], [7], [8], [11]; alcohol use [7]; components of the metabolic syndrome [4]–[11]: BMI, waist-hip ratio, diabetes, fasting glucose, total cholesterol to HDL ratio, triglycerides), for surrogate markers of adiposity (leptin [4], IL-6 [27], [28], adiponectin [29], [30], ghrelin [31], [32]), and for other markers of liver function (bilirubin, GGT, albumin), the association of rising age with decreasing ALT remained significant (p<0.0001, Table 2). Correspondingly, the extreme values of ALT (95^th percentile cutoff points for upper limit of ALT, Figures 1 and 2) as well as the prevalence of elevated ALT (p<0.0001, Figure 3) both decreased with rising age as well. These data suggest that age is an independent and robust predictor of serum ALT within normal range as well as of elevated serum ALT, and this association is independent of adiposity, known metabolic correlates of ALT, and possibly liver function. We also found that serum albumin declines with increase in age, perhaps related to a decline in muscle mass. Serum GGT did not decrease with increase in age in unadjusted analyses but after adjustment for metabolic correlates it also showed a decrease with age. Bilirubin increased with increasing age.

Speculations on Causes and Implications for Future Research

We initially hypothesized that perhaps this trend may be related to decreasing adiposity with advancing age, leading to a decreased prevalence of nonalcoholic fatty liver disease. In analysis of our cohort characteristics, while BMI decreased with age, waist-hip ratio, and IL-6 increased with age, suggesting that central obesity (a component of the metabolic syndrome) increased with age. This finding is somewhat contrary to our hypothesis. These age-related anthropometric and cytokine changes are complex and do not account for the decline in serum ALT. Furthermore, age retained a clinically and statistically significant association with ALT despite multivariable adjustment for these metabolic characteristics and biomarkers.

Another potential explanation is that a decrease in ALT signifies a true decrease in prevalence of liver disease. While the prevalence of significant alcohol use in our cohort did decline with older age, peak consumption occurred at ages after ALT levels started to fall. Furthermore, the trend of decreasing ALT with age persisted after adjusting for alcohol intake, suggesting that alcohol consumption alone does not account for the decrease in ALT with age.

Information regarding viral hepatitis was not available in our study cohort, therefore these participants could not be excluded. Theoretically, a higher burden of chronic viral hepatitis in younger individuals could lead to higher ALT levels in this age group. However, data from NHANES suggests that this is not the case. The prevalence of hepatitis B infection was found to increase with increasing age among Caucasians [35]. While hepatitis C prevalence decreased among Caucasians aged 50 and older, the prevalence rate was only 0.7% [36], therefore any effects of decreasing hepatitis C prevalence would be offset by increasing hepatitis B prevalence, making the overall contribution of viral hepatitis to population ALT trends minimal.

Decreased prevalence of liver disease may also reflect selective survival bias, whereby those with high levels are more likely to have died. A study of 8043 construction workers by Arndt et al. [33] found that elevated liver enzymes predicted a significantly increased risk of all-cause mortality. Adams et al. [34] found that mortality was significantly higher in community-dwelling patients with NAFLD compared to the general population. Due to the cross-sectional nature of this study, we cannot exclude this possibility. Alternatively there is a yet unidentified lifestyle or clinical factor which confers protection to liver disease as one ages.

Another possibility is that decreasing ALT signifies a decrease in the mass or function of the normal liver. This is plausible given that albumin levels decreased with age and bilirubin levels increased with age. Both albumin and bilirubin provide information regarding functional status of the liver and are considered to be true liver function tests. Studies comparing young and old livers in rats showed that older livers have slower and weaker regenerative capacity, a decrease in homeostatic capacity, and a lower inflammatory response rate [37]. In rat models of liver transplantation, aged livers showed a reduced organ weight, increased hepatocyte degeneration, and increased fibrosis [38], [39]. Similarly in humans, older livers show a progressive decrease in size and blood flow, and changes related to the accumulation of oxidative stress [40], [41], [42]. In studies by Elinav et al. [43] and Le Couteur et al. [17], an ALT value below the median was a strong and independent predictor of mortality in community-dwelling elderly men. In our study, modest decreases in albumin and GGT and increases in bilirubin were observed with increasing age after adjustments for sex, alcohol use, metabolic syndrome traits, and surrogate markers of adiposity, suggesting that a decrease in liver function may indeed be present. However, bilirubin, GGT, and albumin are also complex biomarkers and may not solely reflect hepatic function. Furthermore, the trend of decreasing ALT with increasing age remained significant after adjusting for bilirubin, GGT, and albumin.

An additional possibility is that the prevalence of liver disease is the same or perhaps higher in elderly subjects, but the ALT is not a reliable marker of hepatocyte injury. In our study, age was associated with increasing central obesity, systolic blood pressure, and prevalence of diabetes, all factors associated with the metabolic syndrome and NAFLD. Although ALT is frequently used in the evaluation of NAFLD, it has been shown to correlate poorly with liver histology in subjects of all ages [44], [45]. This lack of correlation with ALT levels in the elderly could be increased in part due to a decrease in the inflammatory response of the older liver, as discussed above. Others have suggested that elderly subjects with NAFLD tend to have more fibrosis on liver biopsy compared to younger subjects who tend to have more steatosis or steatohepatitis. Frith et al. [46] examined 351 consecutive patients with biopsy-proven NAFLD, and found that age >60 was significantly associated with fibrosis. Similar results were found by Angulo et al. [47] and Miyaaki et al. [48].

Finally, ALT was a marker of age independent of other liver function tests, including bilirubin, GGT, and albumin. Others have also speculated that ALT may be a novel biomarker of aging [17].

Strengths and Limitations

The strengths of this study include the use of a population-based, well-characterized cohort of healthy, community-dwelling elderly men and women. Analysis of data obtained from a research clinic visit 12–15 years after the initial establishment of the cohort allowed the unique opportunity to study an older group of individuals. One potential limitation of our study is that information regarding chronic liver diseases, such as viral hepatitis, autoimmune hepatitis, or metabolic liver diseases, was not available, thus we were not able to exclude these individuals. However, these conditions are not so common that they would be expected to influence the results. Our study cohort is fairly uniform (predominantly Caucasian, middle to upper-middle class), suggesting good internal validity of the findings. However, generalizability of these findings in other ethnic groups or socio-economic classes would require further studies in other more diverse cohorts.

In conclusion, ALT levels were not constant, but decreased with increasing age for both men and women, independent of components of the metabolic syndrome, surrogate markers of adiposity, and other markers of hepatic function. As a consequence, an ALT value which is considered normal for a younger individual may fall outside of 2 standard deviations for an older individual. The reasons for these differences and the clinical implications of decreasing ALT with age remain to be determined. Future longitudinal studies are needed to confirm our findings and examine the factors that explain the association between the decline in serum ALT with rising age.

Author Contributions

Conceived and designed the experiments: RL. Performed the experiments: RL. Analyzed the data: RB RL. Contributed reagents/materials/analysis tools: RL. Wrote the paper: MD EBC RL. Critical review of the manuscript: EBC.

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How to Determine Voice Range – SAMESOUND

Knowing your own voice range is useful for every musician. It’s not just about vocalists, but about all people involved in music – composers, guitarists, pianists. Knowing the range helps to write music in comfortable keys (or choose minus in the right keys), as well as to process vocals in such a way as not to break the ligaments. SAMESOUND.RU explains how to determine the range of a voice in order to correctly tell about your own vocals.

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How to describe your own voice?

Imagine that a musician responded to an ad from a local band looking for a guitarist with a good voice. The band members ask the musician what his voice is. How do you answer this question?

There are three ways to describe your vocals:

1. Compare your voice with another vocalist. The method is known to be a failure, since no one will believe that you sing the same way as Robert Plant;
2. Give a general description of your vocals. For example, say that you are a lyric baritone, rock tenor, or rock alto. This description is easier to understand, but does not provide useful information;
3. Explain the range of your voice, noting the lowest and highest note you can sing. This is the most informative and normal way of describing vocals.

Despite the clarity of the third method, musicians often give incomplete information about the vocal range. Many students who come to me say that they can sing all notes from lower C to B flat, but they do not specify which octaves are in question.

How to determine the range of a voice?

To accurately determine the range of your voice, it is enough to turn to music theory and the octave system of grouping notes. All sounds that we can use in music and which are distinguishable by the human ear are divided into 9 octaves. A number is attached to each note C, indicating the octave to which it belongs.

Digit	Octave Name
0	Subcontractava
1	Controctava
2	Large octave
3	Small octave
4	First octave
5	Second octave
6	Third octave
7	Fourth octave
8	Fifth Octave

Thus, Before the subcontroctave will be denoted as C0, Before the contractave – C1, and so on.All other notes within the octave are also indicated by the corresponding number: F of the controctave – F1, G of the first octave – G4, E of the fifth octave – E8. The C note of the first octave is in the middle of the 88-key keyboard and is often taken as the starting point (also called Middle C in Western musical tradition).

The range of the voice can be determined using the piano or the Piano Roll in the DAW. Start your search for sounds you can sing from C4.If you can sing this sound cleanly, move down and then up, checking the notes available to your voice. The last sounds from above and below that you were able to sing cleanly and without discomfort for yourself and your vocal cords are the boundaries of the vocal range.

Majority of voices refer to the common boundary from C2 to F3 octave (F6). At the same time, a number of sub-bands have been introduced within the C2-F6 range, which make it possible to more accurately characterize the vocals.

Minor octave A and B notes (A3, B3) and first octave Do and Re notes (C4-D4) are available to all people.Men and women with any voice sing these notes cleanly.

Despite tight sound delineation, you can play notes above or below a certain range without difficulty. However, the range of the voice includes only those notes that you can sing with ease and without discomfort in any situation.

Name	Accessory	Notation	Notation decoding
Bass	Male	E2-D4	From E large octave to D first octave
Baritone	Male	F2-G4	Large Octave F to 1st Octave Sol
Tenor	Male	A2-C5	From A to the second octave
Viola	Female	E3-G5	Minor E to Second Octave Sol
Mezzo-soprano	Female	E3-B ♭ 5	E minor octave to B flat second octave
Soprano	Female	G3-C6	Minor Salt to 3rd Octave

Each voice has many subtypes that refine the range of notes available (for example, baritone is subdivided into lyric, dramatic, and tenor baritone), but such refinements are not practical for ordinary musicians.

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90,000 Ranges of singing voices. What are the different ranges of operatic voices?

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Are you dreaming of becoming a singer? First you need to understand the many subtleties of this work. You should also know the basic ranges of singing voices, how they are measured and how to develop them.

What is the range

Range is the audio volume.These are the singer’s potential to hit certain notes. We all have a certain range from birth. It can be developed into several tones if necessary.
Obviously, the frequency range of the voices of men and women is different. This is noticeable even in casual conversation. Men have a harsher voice. This is due to the thicker vocal folds that are given to them from birth.

Register – a specific area of ​​the sound volume. It can be top, middle, or bottom. Used as a standalone voice measurement capability.

Female and male singing opportunities are divided into several types.

Bass, baritone and tenor are characteristic of the strong half of humanity. Accordingly – low, medium and highest. Girls are characterized by contralto, mezzo-soprano, soprano. The gradation is the same as for male voices: from lowest to highest.

How to find out the boundaries of your range

First, you need to understand the basic difference between singing and sound ranges.In ordinary life, we are able to make various sounds: from a whisper to loud exclamations of joy and happiness. Such high or, on the contrary, low sounds can hardly be reproduced in singing.

The lowest and whistling register of the audio range is not used for singing.

There are several ways to discover the limits of your vocal abilities. This can certainly be done at home. You need to go to the piano and start chanting in accordance with the increase in the sound of the instrument (or decrease in the sound).When you can no longer sing higher or lower – this is the limit of your capabilities today. B

But there is another, more reliable and reliable way – visiting the phoniator. He will give a full consultation and tell you whether it makes sense to develop your own capabilities, and if so, towards the upper or lower case. However, you can slightly lower the sound of your own voice with the help of special exercises.

What is the largest voice range?

There are 8 octaves in total.The singer from St. Petersburg got into the Guinness Book of Records as the owner of the most unique voice on earth.

Tatyana Dolgopologova has an amazing range – 5 octaves and 1 tone. There is hardly a person who can surpass her capabilities.

Modern singers have an average range of 2 octaves. This is enough for full-fledged work on the stage, and it is up to this level that it can be developed.

Of course, it would be nice to be equal to the stars of the world magnitude.So, for example, Whitney Houston’s voice range was, no less, FIVE octaves. Thanks to her magnificent voice, the singer, who made a world tour six times in her life, was greeted with delight in any country of the world. And the inimitable charismatic Freddie Mercury with a voice range of 3 octaves mesmerized multimillion-dollar stadiums. Even Montserrat Caballe sang with the Queen band. Unfortunately, this kind of talent cannot be developed, it is an invaluable gift of Mother Nature. If you are one of the happy owners of such a gift, then you need to take care of it: it can be quite difficult to restore the vocal cords in case of damage.

Female and male voices

The modern classification of voices according to the range of pitch divides them into male, female and children’s. Viola and treble are distinguished among children. The range of male voices is subdivided into bass (low), tenor (high) and baritone (medium in pitch). The ultra-low bass-profundo and the ultra-high tenor-altino are worth noting separately.

Low contralto, high soprano and medium-high mezzo-soprano are represented in the range of the female voice. The most famous contemporary singers, whose operatic voices and soprano range amazed the imagination and delighted the ears of many admirers, should be noted our compatriot Antonina Nezhdanova, Italian Amelita Galli-Curci and Greek Maria Callas.The contralto is the least common among singers. However, it was for this voice that the famous Rimsky-Korsakov wrote Lel’s songs from The Snow Maiden. And Olga’s part in “Eugene Onegin” was also created for this thick, incredibly rich female voice, captivating the very soul of a diligent listener. The basis of beautiful vocals is correct breathing. They study him from childhood. Breathing exercises for children are an excellent preparation not only in terms of singing, but also an important component of physical health in general.

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Subtleties of working with line breaks in Excel

Line breaks within one cell, added using the Alt + Enter keyboard shortcut, are quite common and common. Sometimes users make them themselves to add beauty to long text. Sometimes such transfers are added automatically when unloading data from any work programs (hello 1C, SAP, etc.)The problem is that you then have to not just admire such tables, but work with them – and then these invisible hyphenation symbols can become a problem. Or they may not – if you know how to handle them correctly.

Let’s take a closer look at this issue.

Remove line breaks by replacing

If we need to get rid of hyphenation, the first thing that usually comes to mind is the classic find and replace technique.Select the text and then call the replacement window by pressing Ctrl + H or through Home – Find & Select – Replace (Home – Find & Select – Replace) . One problem – it’s not very clear how to enter in the top field Find what our invisible line feed character. Alt + Enter here, unfortunately, no longer works, you cannot copy this character directly from the cell and paste it here either.

The combination Ctrl + J will help – it is this that is an alternative to Alt + Enter in dialog boxes or Excel input fields:

Please note that after you place the blinking cursor in the upper field and press Ctrl + J, nothing will appear in the field itself.Do not be alarmed – this is normal, the symbol is invisible 🙂

In the bottom field Replace with , either do not enter anything, or enter a space (if we want not just to remove the hyphens, but replace them with a space so that the lines do not stick together). It remains to click on the button Replace All and our hyphenation will disappear:

Nuance : after performing the replacement, the invisible character entered with Ctrl + J remains in the field Find and may interfere in the future – do not forget to delete it by placing the cursor in this field and several times (for reliability) pressing the Delete keys and Backspace.

Remove line breaks with formula

If you need to solve the problem with formulas, then you can use the built-in function CLEAN , which can clear the text of all non-printable characters, including our ill-fated line breaks:

This option, however, is not always convenient, since lines after this operation can be glued together. To prevent this from happening, you need not just remove the hyphen, but replace it with a space (see.next point).

Replace line breaks with the formula

And if you want not just to delete, but to replace Alt + Enter with, for example, a space, then you will need another, slightly more complex construction:

To set the invisible hyphen, we use the function CHAR , which displays the character by its code (10). And then the function SUBSTITUTE looks for our hyphens in the original data and replaces them with any other text, for example, a space.

Division into columns by line break

Familiar to many and very convenient tool Text by column from the tab Data (Data – Text to Columns) can also work great with line breaks and split text from one cell into several, breaking it by Alt + Enter. To do this, at the second step of the wizard, you need to select a variant of the custom separator character Custom and use the Ctrl + J key combination already familiar to us as an alternative to Alt + Enter:

If your data may contain several line breaks in a row, you can “collapse” them by checking the box Treat consecutive delimiters as one .

After clicking on Next (Next) and going through all three steps of the wizard, we will get the desired result:

Please note that before performing this operation, you must insert a sufficient number of empty columns to the right of the split column so that the resulting text does not overwrite the values ​​(prices) that were on the right.

Line division by Alt + Enter via Power Query

Another interesting task is dividing the multi-line text from each cell not into columns, but into rows:

It takes a long time to do this manually, it is difficult with formulas, and not everyone can write it with a macro.But in practice, such a task occurs more often than we would like. The simplest and easiest solution would be to use for this task the capabilities of the Power Query add-in, which has been built into Excel since 2016, and for earlier versions 2010-2013 it can be downloaded for free from the Microsoft website.

To load the raw data into Power Query, you must first convert it to a smart table by pressing Ctrl + T or pressing Format as Table on the Home – Format as Table tab.If for some reason you do not want or cannot use smart tables, then you can work with stupid ones. In this case, simply select the original range and give it a name on the Formulas – Name Manager – New tab .

After that, on the Data tab (if you have Excel 2016 or newer) or on the Power Query tab (if you have Excel 2010-2013), you can press the button From Table / Range to load our table into Power Query editor:

After loading, select the column with multi-line text in the cells and select the command on the Main tab Split Column – By delimiter (Home – Split Column – By delimiter) :

Most likely, Power Query will automatically recognize the division principle and will insert the invisible line feed symbol # (lf) (lf = line feed = line feed) into the delimiter input field.If necessary, other characters can be selected from the drop-down list at the bottom of the window, if you first enable the checkbox Split by special characters .

To keep everything split into rows and not columns, remember to toggle the By rows selector in the advanced options group.

It remains only to click on OK and get what you want:

The finished table can be unloaded back to the sheet using the command Close and Load – Close and Load into… on the Home tab (Home – Close & Load – Close & Load to …) .

It is important to note that when using Power Query, keep in mind that when the source data changes, the results are not automatically refreshed. they are not formulas. To update, be sure to right-click on the summary table on the sheet and select the command Refresh or press the button Refresh all on the Data – Refresh All tab.

Macro for dividing into lines by Alt + Enter

For completeness, let’s mention the solution to the previous problem with the help of a macro. Open the Visual Basic editor using the button of the same name on the tab Developer or the Alt + F11 keyboard shortcut. In the window that appears, insert a new module through the menu Insert – Module and copy the code below there:

 Sub Split_By_Rows ()
    Dim cell As Range, n As Integer

    Set cell = ActiveCell

    For i = 1 To Selection.Rows.Count
        ar = Split (cell, Chr (10)) 'divide the text by hyphenation into the array
        n = UBound (ar) 'define the number of fragments
        cell.Offset (1, 0) .Resize (n, 1) .EntireRow.Insert 'insert blank rows below
        cell.Resize (n + 1, 1) = WorksheetFunction.Transpose (ar) 'enter data from the array into them
        Set cell = cell.Offset (n + 1, 0) 'move to the next cell
    Next i
End Sub
 

Return to Excel and select the cells with multiline text that you want to split.Then use the Macros button on the Developer – Macros tab or the Alt + F8 keyboard shortcut to run the created macro that will do all the work for you:

Voila! Programmers are, in fact, just very lazy people who better strain themselves once, so that they do nothing later 🙂

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Windchill ALT (formerly Relex ALT) – Accelerated Life Testing

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Windchill ALT (formerly Relex ALT) – Accelerated Life Testing – Data Sheet

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Windchill ALT (formerly Relex ALT), or Accelerated Life Testing, enables the statistical methods used to identify characteristic failure behavior from products exposed to higher than normal stresses.

© 2011, Parametric Technology Corporation (PTC). All rights reserved. Information described herein is furnished for informational use only, is subject to change without notice, and should not be construed as a guarantee, commitment, condition or offer by PTC. PTC, the PTC Logo, Windchill, and all PTC product names and logos are trademarks or registered trademarks of PTC and / or its subsidiaries in the United States and in other countries. All other product or company names are property of their respective owners.The timing of any product release, including any features or functionality, is subject to change at PTC’s discretion.

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GMstrings®) / Production of musical strings

Babichenko D.L.
founder of the string company “Mister Musician”

For some reason, no one has to prove that the violin viola is the same full-fledged instrument as the violin – it is a full-fledged member of the classical quartet, concerts and sonatas are written for it, and wonderful musicians, of whom Yuri Bashmet first comes to mind, perform them.And what, tell me, comes to mind when you mention the balalaika alto or second, what and by whom are they glorified? That’s it. For 120 years (!) From the moment they were born, they have not managed to advance in their development by a single millimeter. No one stutters about any solo parts, and even more so about concerts and sonatas for them, unlike, for example, the alto domra, which, having appeared in the orchestra of V.V. Andreev ten years later, the viola balalaika, in recent years more and more successfully breaks through a solo career and is already acquiring its own unique repertoire.The progress of the second and the viola is also not conducive to the fact that they use stiff steel strings with a rather strong tension (50-100% higher than that of a primo), as well as huge, by the standards of other instruments, fluctuations in the scales (see figure below).

Not only do each of the scales of the orchestral balalaikas “dance” in a huge range, but they also intersect ^[1] ! But we are not talking about amateur instruments, but about the most real professional ones.On the one hand, it is ridiculous, on the other, it is a shame for the low level of Russian Lutiers ^[2] , who still do not receive special education, and on the third, the picture is too egregious to be explained by such well-known reasons as:

• desire to change the tension force of standard strings when it is impossible to have strings of different types of tension;
• The naive belief of poorly educated Lutiers that changing the length of the scale can dramatically improve the sound of the instrument;
• Manufacturing of the instrument / scale at the hand of the customer, regardless of official standards.

Obviously, the same reasons apply to the domra family, but there the scatter is noticeably smaller, and the scales of neighboring instruments do not intersect. For a long time this mystery haunted me until I found out that there is another reason for the confusion with orchestral balalaikas – a historical one. Finding it helped the articles of the well-known Moscow luther Valery Grebennikov about the history of the revival of balalaika by V.V. Andreev, but mainly – the studies of the musicologist Boris Tarasov, published in the Narodnik magazine in 2004-2007.Personally, I no longer doubt that the flawed state of the balalaika seconds and viola, leading to their degradation, lies in the history of the appearance of these instruments at the end of the 19th century. And it was like this.

In 1883 (1884), a very young, talented and ambitious Vasily Andreev set himself an ambitious goal – to make a professional musical instrument out of a simple village “strummer” that could take its rightful place not only in Russian, but also in world culture. At that time, he could hardly think about seconds, violas and other instruments of the future orchestra – in order to “bring to mind” one primo, he had to do a lot – to conduct research work and among the numerous instrument variants existing among the people to determine the optimal shape, the number of strings, their structure, scale, make a lot of improvements in the design, abandon traditional knitted frets, start using better materials in production, apply technologies for the manufacture of bowed instruments, guitars and mandolins … was created, largely thanks to the collaboration with the violin luther V.Ivanov and the owner of the workshop for the production of stringed musical instruments F.S. Passerbsky. The latter, being interested in receiving new orders for the workshop, helped Andreyev in the period from spring 1887 to spring 1888 to develop and manufacture: prima balalaika (Andreyev’s first instrument with 12 metal frets), piccolo, alto, bass (later treble, tenor , and in 1898 a double bass). It is not difficult to guess what the quality of the new products was and the thoughtfulness of their design, tunings and lengths of the scales – it is surprising how it was possible to make so many different instruments in such a short time, and even have time to master the game on them.But the enthusiasm of Andreev and his fellow followers was so great that a miracle happened, and the early “Circle of fans of playing the balalaikas” not only took place, but even became famous, although, in addition to problems with the quality of instruments, the level of skill of the amateur circles was not high – learning plays went “by hand” and “by ear”.

A completely different, truly professional approach appeared a few years later at a new stage in the development of the circle with the appearance in it, at the invitation of Andreev, of a talented musician, a student of A.K. Lyadov and N.A. Rimsky-Korsakov Nikolai Petrovich Fomin ^[3] . The services of this humble man to Russian music are often unfairly attributed to V.V. Andreev himself – it is a shame that his role in the creation of the Great Russian Orchestra is still poorly covered by music historians and is still awaiting serious research.

In his “Life” ^[4] Nikolai Petrovich recalls: “In October 1889, V.V. Andreev was talented, sensitively musical, but absolutely musically uneducated, realizing all his inconsistency in the development of his circle, having heard about me as an educated musician and connoisseur of Russian music, he turned to me with a request for cooperation and taking over the musical development and leadership of the circle. “It is Fomin, not Andreev, who step by step transforms the circle of amateurs into a professional orchestra, calculates the scale and scales of the new domra family, and gradually introduces the harp and wind instruments into the orchestra. “In 1896, I finally established the nomenclature of instruments, the role of each instrument in the orchestral performance, the form of writing scores.” How simple, one mean phrase (the genre of autobiography does not allow the author to go into details), behind which undoubtedly months of hard work are hidden.But nevertheless, it is one thing to create a new group of domras, relying on the laws of building a symphony orchestra, and another to try to fit into the orchestra that is being created, an already existing bulky group of balalaikas, ^[5] made by talented, but still amateurs, and besides hastily on a wave of enthusiasm without considering many factors. I think Fomin wondered for a long time over how to solve the problems of unnecessary balalaikas in the least painful way, but, as time has shown, even he did not succeed in everything. ^[6] He abolished balalaikas treble, tenor, a little later piccolo, ^[7] changed the scale of the alto and added a new instrument – the second. ^[8]

Just say – “I changed the tuning of the viola”, but this automatically entailed a change in the scale of the instrument. And if in the orchestra with the help of the ingenious S.I. Nalimov it was relatively easy to make new ones or to rework old violas, then what was to be done with hundreds, if not thousands of instruments already released “to the people” by factories and workshops, for example, the same Paserbsky? ^[9] Who would have carried them for repairs of their own free will, or, moreover, threw them away and began to buy new ones with corrected scales? They rebuilt it in a new way – the strings did not break, that’s wonderful, we will continue to play.Here it is – the main reason that the balalaikas alto and second, which are already not the most perfect musical instruments, still have an incredible range of scale fluctuations up to crossings. What a pity that Andreev, who possesses many positive qualities, but did not have special knowledge, did not get to know Fomin even before the creation of the “circle”. This would allow avoiding many mistakes and unnecessary costs when solving such a complex and responsible task as designing new musical instruments, and today with scales and tunings, orchestral balalaikas would have the same order as in domras.

The first part of the reform

I propose the following way of correcting the situation to bring orchestral balalaikas out of age-old stagnation and degradation:

• to abandon unison strings on the viola, changing its tuning from the current LYA-MI-MI (hereinafter, the notes of the scale are indicated from the upper, thinnest string) to the fourth RE-LA-MI like the domra alto; ^[10]
• to mercilessly remove from the orchestra a second, which was not particularly needed before, but with the emergence of the fourth alto, which combines the RE-LA-LA seconds and LA-MI-MI viola into one instrument, and even more so;
• as a quart alto, use modern ones: a second, short-scale alto or even accept (instruments with scales in the range of 450-490 mm), installing smooth (polished) strings on a synthetic base ^[11] on them.

As practice shows, the alto balalaika with soft sensitive strings, not only sounds much better, but also allows you to use all the playing techniques in the right hand as an example, refusing to use the pick. If the proposed reform in the viola arouses interest and support among the musicians, then conditions will arise that allow the instrument to begin to develop normally. And there it will soon come to the balalaika Bashmetov. As a developer of the Sintal® technology, we are ready to send synthetic strings for the fourth alto free of charge to everyone (see the address for applications).in the CONTACTS section).

The second part of the reform

For faint-hearted balalaika players, please do not read!

However, the reform cannot end on the viola, and here’s why. Some readers may have guessed that, if the fourth viola is successful, the RNI orchestra will have only one instrument that does not have the RE-LA-MI scale. ^[12] This “white crow” will turn out to be the prima balalaika, as a result of which its transition to a unified orchestra structure will be only a matter of time – most likely more than a decade.To make this transition less painful is the task of the second part of the reform. There will be a lot of work for both musicians and Lutiers, since strings alone cannot be done here. We’ll have to create a new instrument with a shorter scale. ^[13] However, this and other technical issues should not cause serious problems (by the way, similar instruments called “quarters” were created at one time, however, without much success, it is possible that due to the use of steel strings), but when mastering a new prima, due to the lack of a teaching methodology on such an instrument, problems will surely arise.Here one can no longer do without the assistance of higher school teachers and balalaika soloists, to whom I and my followers have yet to prove the advantages of the new instrument over the traditional one. I foresee that it will not do without hot battles.

CODA

Finishing the article, I would like to touch upon the history of the question of choosing the balalaika tuning. There is no doubt that whichever of the existing in the eighties of the nineteenth century in Russia options for the system Andreev chose, and there were many, ^[14] that would become academic.So why, at the dawn of his career, young Vasily Andreev, who dreamed of the idea of ​​reviving the balalaika, stopped at the unison version? Accidentally? Of course not – it was this system, as the easiest to learn, that best contributed to the solution of the task set by Andreev to introduce the instrument to the masses. Let us recall his words, which today many have forgotten or do not want to remember, like much of what this outstanding person spoke about:

“An uncomplicated instrument, a melodious motive and ease of playing, which does not require lengthy and difficult preparation, make it accessible to the masses.In three minutes I can teach to play the balalaika “Barynya”. … I regard the success (balalaikas) in an intelligent society as something transient. The place for the balalaika is not here, but among the people, into which it will be brought in through the soldiers who have served their terms, who now have the correct training to play the balalaika ”. ^[15]

“I repeat, we still have to work a lot to raise the musical and cultural level of the people. And the right way for such an increase is to widely attract the masses to active participation in art, through collective music lessons on improved musical instruments that are easily accessible and close in spirit to the people and familiarizing them with a repertoire that is accessible to their understanding. “

However, as we know, the instrument not only did not become widespread, it has long been not even popular, but existing (with rare exceptions) not even in an “intelligent society”, but in a small professional environment. And if we have already come to this historically, then is it not time to put the question like this: what is more important for professionals – in three minutes to learn to play “Lady” or to have an instrument on which you can successfully master a complex, diverse, including symphonic repertoire? If the modern doctrine of instrument development does not differ from the Andreevskaya one and consists in ensuring the mass mastering of the balalaika by the people who do not know any (including musical notation) reading and writing according to the so-called “digital system”, then everything is correct, unison is only to help.Only the train left long ago – the niche of the folk instrument is already occupied by the guitar, and neither the balalaika nor the domra will be able to win it back, either with or without unison.

A collection of pieces from 1898 for self-study of playing on a digital system for an ensemble consisting of small domra and viola, balalaikas: piccolo, prima, second, alto, bass and contrabass.

If, on the contrary, we want to give the professionals the most perfect instrument possible, then it was necessary to get rid of the unison that was already reducing its small range long ago and move to a more progressive quart system, thus bringing Fomin’s half-hearted reform to its logical end.And do not be afraid to touch upon the reform I will accept, which, being the main instrument of the family, needs renewal and full development more than anyone else. In addition, as rightly noted in his article “On some problems of balalaika structure in performing practice” ^[16] the first-class balalaika soloist Denis Pavlov, as far as I know, was the first to suggest abandoning unison strings for example, the quart tuning “allows you to perform with all the literature for balalaika created to date.The only exceptions are chords (…) using the third open MI string, which (…) are extremely rare ”.

In connection with the above, I think that in a professional environment it is high time to raise the question not about whether or not it is necessary to abandon unison in prima, but which of the variants of the quart system for prima is preferable – LA-MI-SI, proposed by Denis Pavlov, or the “general orchestral” RE-LA-MI, for which I am advocating. ^[17]

Footnotes:

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[1] The scale of the balalaika second can be either shorter than the prima or longer than the alto!
[2] I do not like the word “master” that has taken root in Russia, which does not describe the essence of the profession, and often sounds like a mockery.The English word “Luttier” is more suitable for this role, since it is not only accepted all over the world, but also does not carry any ambiguity.
[3] After the death of VVAndreev in 1918, NPFomin was appointed chief conductor of the Great Russian Orchestra.
[4] Narodnik. 2004. No. 2.
[5] By this time there were balalaikas: piccolo, treble, prima, alto, tenor, bass, contrabass (I also came across references to the soprano balalaika). It is obvious (for a professional) that even for an ensemble of amateur musicians, such a number of different types of instruments was too much.
[6] Proposing a more radical reform, with a change in the prima balalaika structure and a complete rejection of unison strings, Fomin could offend the ambitious Andreev, the founder of the balalaika ensemble.
[7] In the 1898 edition of “30 Pieces for Ensembles of Amateurs Playing on a Digital System,” the piccolo balalaika is still encountered. Prima and viola, except for the fact that unison strings, which only prima had before, appeared on two more instruments of the family, so that musicians with prima playing skills would find it easier to master the second and the viola.And it is possible that it was easier for Fomin himself to make arrangements, considering these instruments in combination as one instrument of the RE-LA-MI scale, equal to the domra alto. It is possible that both.
[9] By the time the Great Russian Orchestra appeared in 1896, amateur balalaika ensembles, using instruments of the previous composition and structure, had long been in vogue. Their popularity grew so rapidly that, according to Andreev, in 1898, in the capital alone, over 60 thousand balalaikas and domras were produced annually.
[10] Thank you for the support of this idea, Professor of the Russian Academy of Music. Gnesins Viktor Semenovich Chunin.
[11] At the end of March 2010, GOSPODIN MUZYKANT® (www.gmstrings.ru) began work on the creation of synthetic strings for the balalaika alto system RE-LA-MI using the unique Syntal® technology. We bring to your attention a recording made on June 30, 2010 immediately after the manufacture and installation of the strings on the instrument. Playing a student of the Moscow State Institute of Music. A.G.Schnittke Ivan Vinogradov (“artisan” viola born in 1989 with a scale of 485 mm.)

[12] Today, the Fomin RE-LA-MI quart tuning has the following orchestral instruments: small domra, alto, bass, double bass, balalaika bass and double bass.
[13] As shown by mathematical calculations, “quart prima” should have a scale in the region of 350-370 mm.
[14] According to V. Galakhov’s research, there were the following scales of folklore balalaika: quart with unison, second-third, third-third, third-major, third-fourth, fourth-third, sixth-third.
[15] VV Andreev’s interview to the correspondent of “Petersburg newspaper” (1898)
[16] Narodnik. 2005. No. 4 (52).
[17] In my opinion, the RE-LA-MI tuning has more advantages from orchestral considerations. At the end of November 2010, the first copy of such an instrument was born, which is waiting for its future owner-enthusiast.
On November 27, 2010, an unusual instrument was tested at the firm – the prima balalaika in the RE-LA-MI system. The instrument was designed and manufactured by Lutier Alexander Spustnikov and has a scale of 350 mm.The strings were calculated and made personally by the head of the company GOD MUSICANT® Dmitry Babichenko. The tests of the instrument and strings were carried out by the soloist of the Orchestra named after I. Osipova Dmitry Bazanov, who positively assessed the result of the work, albeit with minor remarks, which were accepted for correction.

Photoshop Hotkeys

Show or hide the Layers palette	F7
View single layer	ALT + click on the eye image in the Layers palette
Create a new layer and set the blend parameters (Blend)	ALT + click on the page thumbnail at the bottom of the Layers palette or CTRL + SHIFT + N
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Clone selection to a new layer	CTRL + J
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One layer up	ALT +]
One layer down	ALT + [
Go to the top layer	SHIFT + ALT +]
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Preserve the transparency of the active layer	/
Convert layer opacity mask to selection outline	CTRL + click on the layer name in the Layers palette
Add layer opacity mask to selection outline	CTRL + SHIFT + click on layer name
Subtract transparency mask from selection	CTRL + ALT + click on layer name
Opacity mask and selection intersection	CTRL + SHIFT + ALT + click on layer name
Move whole layer	Drag with move tool or CTRL + drag with other tool
Move whole layer in 1 pixel increments	CTRL + Cursor key
Move whole layer in 10 pixel increments	CTRL + SHIFT + Cursor key
Move the layer one level forward	CTRL +]
Bring Layer To Front	CTRL + SHIFT +]
Move the layer back one level	CTRL + [
Bring the layer back to position in front of the background layer	CTRL + SHIFT + [
Link layer to active layer	Click in front of layer name
Break the link between the layer and the active layer	Click on the chain icon in front of the layer name
Break links of all layers with the active layer	Alt + click on the brush thumbnail in front of the active layer name
Change the opacity of the active layer in 10% steps	Number key (from 1 to 0) with active selection tool
Change the opacity of the active layer in 1% increments	Two keys in a row with numbers when the selection tool is active
Edit Blend Option for Layer	Double click on the layer name in the Layers palette
Activate mixing mode	SHIFT + ALT + LETTER
Change of mixing modes	SHIFT + + or SHIFT + – with active selection tool
Return to normal mixing	SHIFT + ALT + N
Fuzzy setting in Layer Options dialog	Alt + drag triangular slider
Merge the layer with the next	CTRL + E
Merge linked layers	CTRL + E
Combine all visible layers	CTRL + SHIFT + E
Copy merged selection to clipboard	CTRL + SHIFT + C
Clone layer content to next layer	CTRL + ALT + E
Clone the contents of linked layers to the active layer	CTRL + ALT + E
Clone the contents of all visible layers into the active layer	CTRL + SHIFT + ALT + E
Group adjacent layers	ALT + click on the horizontal line in the Layers palette or CTRL + G
Ungroup adjacent layers	ALT + click on the dashed line in the Layers palette or CTRL + SHIFT + G
Toggle between layer effects in the Effects dialog	CTRL + 1 to CTRL + 5
Toggle between layer effects outside of the dialog	right click on f in the Layers palette
Edit layer effect	Double click on f
Move shadow when Effects dialog is open	dragging in the image window
Block the effect of the last layer	ALT + double click on f
Block the effect of a specific layer	ALT + select a command from the submenu Layers / Effects
Create customization layer	CTRL + click on the page thumbnail at the bottom of the Layers palette
Save a “flat” copy of the image with layers	CTRL + SHIFT + S

Clinical Study Hypertension: ALT-711 – Clinical Trials Registry

Eligibility

Criteria: Inclusion criteria – Men or women over 50 years of age.- Screening diagnosis of isolated systolic hypertension, defined as systolic blood pressure> 150 mm Hg. Art. and a diastolic blood pressure of 140 mm Hg. Art. (measured around the clock on an outpatient basis. Blood pressure monitoring – average daily values). – Baseline systolic blood pressure> 150 mm Hg. Art. And diastolic blood pressure is 9%. – Serum creatinine> 1.7 mg / dL. – History of ketoacidosis or uncontrolled diabetes within the past 2 years.- History of congestive heart failure. – History of stroke or any consequences of transient ischemic attack, reversible ischemia, neurological defect or stroke within the last 12 months. – History of acute myocardial infarction within 6 months prior to study entry. – Any significant abnormalities in the ECG, including second-degree AV block or complete AV block. Any known significant arrhythmia, including atrial flutter, ventricular tachycardia, WPW syndrome. Any hemodynamically significant valvular heart disease.- Any serious systemic disease or disease that may cause difficulty. observing the protocol. – Screening or baseline liver function tests SGOT and / or SGPT> 2.0 times the upper limit of the central laboratory normal range. – Use of systemic and / or inhaled corticosteroids (excluding topical corticosteroids). – Any additional conditions that, in the investigator’s opinion, prohibit the patient from completing the study, or are not in the patient’s best interests.- Use of any investigational drug within 30 days of screening. – Previous exposure ALT-711. – Known seropositivity for HIV or hepatitis C or the presence of superficial hepatitis B antigen. – Pregnancy or active breastfeeding. Female patients of childbearing age (not postmenopausal for at least 5 years or surgically sterilized) must agree not to become pregnant at the time of the study. In particular, they must agree to use an appropriate contraceptive regimen.Acceptable regimens include abstinence, systemic hormones, IUDs, and barrier methods such as cervical caps, male or female condoms, or diaphragms with concomitant intravaginal spermicide. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website