Your hemoglobin A1c (HbA1c) indicates your long-term glucose levels and is used along with other markers to diagnose diabetes. Increased HbA1c in nondiabetics, apart from being a risk factor for diabetes, has also been associated with heart disease and elevated all-cause mortality. Read on to learn about the causes and health risks of high HbA1c.
High Hemoglobin A1c (HbA1c) Causes
High HbA1c Causes
Causes shown here are commonly associated with high HbA1c. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret this test, taking into account your medical history and other test results.
1) Diabetes
HbA1c ≥ 6.5% is a reliable indicator of diabetes [1].
Values over 5.6% indicate prediabetes.
In non-diabetic Japanese health-check examinees who were 30 – 79 years old, the incidence of diabetes increased with increasing baseline HbA1c [2]. In this and other studies, an HbA1c above 5.7% was a suitable value for predicting future diabetes [2, 3].
According to the American Diabetes Association (ADA), 9.3% of the American population is diabetic [4].
2) Being Overweight/Obese
Obesity is associated with impaired glucose tolerance and insulin resistance [5].
A positive energy balance, when there are more calories consumed than spent, is associated with higher HbA1c [6].
Higher body mass index (BMI), waist-to-hip ratio, and waist circumference were all linked to significantly higher HbA1c [7].
3) Smoking
Smoking increases HbA1c levels in both diabetic and nondiabetic people [8, 9].
4) Iron, Vitamin B12, or Folate Deficiency Anemia
Iron, vitamin B12, or folate deficiency anemia can all increase HbA1c levels, irrespective of blood glucose levels [10, 11, 12, 13, 14].
The effect is dependent on the degree of anemia, as a study found that those with mild anemia did not show significant effects on HbA1c [11].
The administration of the deficient nutrient usually decreases the HbA1c back to normal [12, 15]. However, these nutrient deficiencies often have non-dietary causes, such as bleeding or gut disease, that decrease nutrient absorption. That’s why it’s important to work with your doctor to address all underlying health issues.
5) Chronic Disease
Some chronic conditions, such as periodontal (gum) disease, H. pylori infection, and chronic kidney disease increase HbA1c levels [16, 17, 18, 19, 20].
HbA1c levels are often correlated with CRP levels, which are a marker of chronic inflammation, increased in many chronic diseases [21, 22].
Gum Disease
Research suggests there is an association between oral hygiene practice and blood glucose levels in diabetes [23]. Individuals with better self-reported toothbrushing practices tend to have lower levels of blood glucose and HbA1c [23, 24].
An Indian study reported that tooth brushing twice daily was associated with good diabetes control (HbA1c < 6.0%) in both male and female adults with type 2 diabetes [23].
HbA1c is significantly elevated with periodontal (gum) deterioration even in nondiabetics [16, 17]. Studies show that treatments that improve gum inflammatory conditions helped decrease HbA1c levels [25, 26].
H. pylori Infection
Chronic H. pylori infection was associated with high levels of HbA1c and type 2 diabetes in the elderly [18].
A study showed that H. pylori eradication treatment had beneficial effects on insulin resistance and favorably changed HbA1c in patients with normal glucose concentrations [19].
Chronic Kidney Disease
In patients with elevated blood urea due to kidney failure, there is an elevated production of carbamylated hemoglobin, which can make HbA1c results inaccurate [27, 28].
6) Sleep Disorders
Both short and long sleep durations were associated with an increased HbA1c. Similarly, poor sleep quality was associated with a higher HbA1c [29].
The presence of sleep apnea and lower levels of oxygen in the blood were associated with higher HbA1c levels in patients with type 2 diabetes [30]. Sleep apnea is a sleep disorder characterized by pauses in breathing or periods of shallow breathing during sleep.
Type 1 diabetes patients with moderate-to-severe obstructive sleep apnea had a trend toward higher HbA1c [31].
Even in nondiabetic men with obstructive sleep apnea, high HbA1c levels were associated with a more severe disorder [32].
7) Some Genetic Hemoglobin Disorders
Some genetic hemoglobin disorders can falsely increase HbA1c levels, depending on the methods that a laboratory uses for testing [14].
8) Some Drugs
Opiates
Chronic opiate use has been reported to increase HbA1c levels, but the exact mechanism remains unknown [15].
In a study that compared 1.6k people with and 2.8 k people without substance abuse, HbA1c level was elevated in those with substance abuse [33].
Statins
The use of high-potency statins may increase HbA1c levels in people with or without diabetes [34]. A study has shown that In people with diabetes, HbA1c increased by 0.4% after high-potency statin use [34].
Studies also suggest that there is an increased risk of new-onset diabetes with statin use [34]. The effects, though, may vary by drug. HbA1c was significantly increased after 3 months in patients receiving atorvastatin, while levels remained unchanged in those receiving pitavastatin [34].
9) High Bilirubin Levels
An increase in bilirubin levels (hyperbilirubinemia) that often accompanies liver disease can result in falsely elevated HbA1c levels [14].
10) Alcoholism
Heavy alcohol use can falsely increase HbA1c levels. This happens because alcohol products react with hemoglobin in the blood forming hemoglobin-acetaldehyde (HbA1-AcH), which can be mistakenly measured as HbA1c [14, 35, 36].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401751/
Health Risks of High Hemoglobin A1c (HbA1c)
1) Diabetes Complications
A study showed that the incidence of impaired eye and kidney function in 451 patients with type 1 diabetes increased sharply and happened earlier on with increasing HbA1c. None of the patients developed these complications when HbA1c was below 7.6% [37].
The variability of HbA1c levels is equally important. Unstable levels increase the risk of kidney and eye disease and even lower extremity amputation in patients with diabetes [38, 39, 40, 41].
High HbA1c was also associated with nerve pain. In a study of 417 diabetics, those reporting pain were more than twice as likely to have HbA1c levels > 8% (64 mmol/mol) [42].
Both high HbA1c levels and their variability (instability), could predict the development of kidney disease in T1DM and T2DM patients [38].
2) Cognitive Impairment
Higher HbA1c was associated with poor cognitive performance in a study of over 1100 healthy middle-aged people [43].
Higher levels were also associated with poorer baseline episodic memory and greater episodic memory decline in 2 studies with over 5k adults [44, 45]. This association was more pronounced in women [45].
Memory and learning problems in 233 children and adolescents were associated with HbA1c > 8.8% (73 mmol/mol) [46].
3) Dementia
Higher levels of HbA1c have been associated with an increased risk of dementia and Alzheimer’s in the elderly.
In a study of over 1.3k elderly, HbA1c levels ≥6.5% were associated with a 2.8-fold increased risk of all-cause dementia and Alzheimer’s. HbA1c levels ≥7% were associated with a 5-fold increased risk of all-cause dementia and a 4.7-fold increased risk of Alzheimer’s [47].
4) Hardening of the Arteries (Atherosclerosis)
There is an interwoven relationship between unsatisfactory blood sugar levels, low-grade inflammation and low HDL cholesterol on the hardening of the arteries in type 2 diabetes [48].
In 77 adolescents with type 1 diabetes, arterial stiffness was directly related to high HbAc1 [49].
Arterial stiffness positively correlated with both HbA1c and duration of diabetes in 1000 subjects with diabetes and elevated blood pressure [50].
High HbA1c was also associated with a higher atherosclerotic burden in nondiabetic patients. In 6.5 nondiabetics, high-normal HbA1c levels were independently associated with arterial stiffness [51, 52].
5) Heart Disease
Increased risk of heart disease was found with higher HbA1c levels in both those with established diabetes and in non-diabetic adults [53, 54, 55].
HbA1c showed a direct correlation with blood cholesterol, triglycerides, and LDL in diabetic patients. All three are risk factors for heart disease [56].
Chronically elevated glucose, measured by HbA1c, was also disruptive for the heart function [57].
However, lower HbA1c was also reported to increase the risk of cardiovascular disease in some studies. In one study of over 8.6k people, both HbA1c < 6% as well as HbA1c > 10% were independently associated with the risk of heart failure [58].
6) Fatty Liver
Fatty liver is associated with higher HbA1c [59].
In nondiabetic individuals, the risk for non-alcoholic fatty liver disease (NAFLD) increased with increasing HbA1c levels, independent of obesity and other metabolic components [60, 61].
In another study, the prevalence of NAFLD was significantly higher in subjects with HbA1c ≥ 6.5% [61].
7) Fatigue (in Diabetes)
About three-quarters of patients with type 1 diabetes suffer from persistent fatigue. Higher HbA1c was weakly associated with fatigue [62].
In patients with type 2 diabetes, with an HbA1c greater than 7%, fatigue was indirectly related to HbA1C. This relationship was mediated through diabetic symptoms, depression and diabetes distress [63].
8) Anxiety and Depression (in Diabetes)
In over 800 diabetics, depressed mood, sleeping difficulties, appetite problems, and suicidal ideation correlate with higher baseline HbA1c levels and higher HbA1c values at 1-year follow-up. These associations were more pronounced in type 1 diabetes than in type 2 diabetes patients [64].
High levels of HbA1c (HbA1c≥9.0%) were associated with a greater risk of anxiety and depression in a study of 491 African diabetic men [65].
9) Bone Loss (in Diabetics)
Bone loss is a complication of diabetes characterized by osteoporosis, increased risk for bone fractures and alterations in bone metabolism [66].
Osteocalcin (OC) is a bone-specific protein produced by bone cells, involved in the regulation of glucose and energy metabolism [66]. This is a bone-building protein and correlates well with a person’s bone mineral density (BMD). In type 1 diabetes of long duration, lower osteocalcin in the blood was associated with higher HbA1c [66].
Similarly, in type 2 diabetic patients, lower bone mineral density was associated with higher HbA1c [67].
Also, higher bone resorption was independently associated with higher HbA1c in women [68].
10) Hearing Loss
High HbA1c was associated with increased hearing loss in a study of 7.5 nondiabetics [69].
11) Irregular Menstrual Cycles
In one study, girls with type 1 diabetes and HbA1c levels of 7.6 – 8.9% had increased cycle duration, menstrual cycle variability, and infrequent periods (oligomenorrhea). For each point of increase in HbA1c, the menstrual cycle duration increased by 5.1 days [70].
12) Cancer
Studies report that higher HbA1c levels are associated with higher incidence and/or mortality risk of cancers. In a systematic review of 19 studies, elevated HbA1c levels were associated with a higher risk of developing colorectal, pancreatic, respiratory and female genital tract cancers [71].
In a study of over 300 people with colorectal cancer those with poorly controlled type 2 diabetes, with HbA1c > 7.5, had more advanced colorectal cancer, a younger age of onset and poorer 5-year survival. Additionally, in patients with type 2 diabetes who have colorectal cancer, unsatisfactory blood sugar levels are associated with a clinically more aggressive course of the disease [72].
Low Hemoglobin A1c (HbA1c) Causes
Low HbA1c Causes
Causes shown here are commonly associated with low HbA1c. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret this test, taking into account your medical history and other test results.
1) Conditions that Decrease or Destroy Red Blood Cells
Conditions that decrease the number of red blood cells, such as blood loss, donation, or transfusion can falsely decrease HbA1c levels despite possibly elevated blood glucose [15, 73].
Destruction of red blood cells (hemolysis) that can occur in infections, autoimmune diseases, tumors, and as a side effect of some drugs also decreases HbA1c [15].
An enlarged spleen is another condition that destroys red blood cells and decreases HbA1c [14].
2) Alcoholism
Excessive alcohol consumption can decrease HbA1c levels despite elevated blood glucose because it may interfere with the binding of glucose to hemoglobin. It also may have an effect by lowering blood glucose levels [74, 75, 76].
3) Liver Disease
HbA1c can be lower in chronic liver disease [77].
The mechanisms involved are still not known, but scientists suggest it may be a combination of abnormal red blood cell turnover and function (e.g., anemia and iron overload) and viral infection [77].
4) Pregnancy
HbA1c can be lower in the second trimester of pregnancy [14].
5) Some Drugs and Supplements
Any drug which causes the rupture or destruction of red blood cells can potentially lower HbA1c by increasing the proportion of younger cells in the blood. Dapsone, ribavirin, antiretroviral, and sulfonamide drugs have all been reported to reduce the HbA1c in this manner [15].
Hydroxyurea is used for the treatment of some leukemias and sickle cell disease. This drug can significantly reduce the number of blood cells and causes a decrease in HbA1c levels [15].
Chronic use of aspirin has been reported to falsely decrease HbA1c [15]. However, aspirin can also modestly, in a way that is not clinically relevant, increase HbA1c levels in some cases [78].
Vitamin E can decrease the binding of glucose to hemoglobin, falsely decreasing HbA1c [14].
6) Some Genetic Hemoglobin Disorders
Some genetic disorders such as sickle cell anemia and thalassemia can cause falsely low HbA1c, depending on the method the laboratory uses for the test [15].
Hemoglobin A1c and Lifespan
Several studies observed that higher HbA1c levels (≥6.5%, 48 mmol/mol) were associated with increased mortality, whereas others failed to find any significant associations with mortality across the whole HbA1c range. Furthermore, some studies also found increased mortality in people with lower HbA1c values [79].
High HbA1c May Increase Mortality
Higher HbA1c levels were associated with increased mortality from all causes among nondiabetics, in a meta-analysis of 11 studies with over 113k people [79].
A study of over 2.1k people who had a stroke reported that the risk for all-cause mortality was significantly increased when HbA1c level was > 5.5% compared to HbA1c < 5.5%, and it further dramatically increased 2 – 3 times in the highest HbA1c group ≥ 7.2% [80].
The American Diabetes Association (ADA) estimated that the risk of diabetes-related mortality increased by 25% for each 1% increase in HbA1c. It has also been estimated that each percentage point increase in HbA1c corresponds to a 35% increase in the risk of heart disease and an 18% increase in the risk of heart attack [56].
Why does elevated HbA1c relate to mortality? Ample evidence shows that elevated glucose can increase oxidative stress. Oxidative stress then damages blood vessels, contributing to heart disease. Oxidative stress can also damage DNA, potentially resulting in gene mutation and cancer development [79].
Low HbA1c May Also Increase Mortality
Increased mortality was also reported for HbA1c levels below the optimal range in diabetics. Some reported an increased risk for heart disease or death among nondiabetic subjects with HbA1c levels below 4.0% (20 mmol/mol), 4.8% (29 mmol/mol), 4.9% (30 mmol/mol) or 5.0% (31 mmol/mol) [81, 82].
Some explanations for the low HbA1c and mortality relationship, include: being underweight or malnourished, inflammation, anemia, high alcohol consumption, liver disease and chronic kidney failure [81].
It appears that malnutrition, inflammation, and functional decline are characteristics shared by the populations that showed increased mortality and low HbA1c. Thus, frailty or decline may be the main confounding factor explaining the relationship between increased mortality risk and low HbA1c [83].
In one study, where HbA1c < 5% was associated with adverse outcomes in nondiabetic people, a link to inflammation and autoimmunity was suggested [82].
Takeaway
Though HbA1c is a direct measure of long-term sugar levels, diabetes is not the only cause of high values. Sleep disorders, gum disease, H. pylori infections, chronic inflammation, and anemia can also increase HbA1c. Additionally, high levels are linked with metabolic syndrome and obesity, which often progress to type 2 diabetes. High HbA1c levels can have many negative effects on your health, whether you have diabetes or not. People with high levels are at an increased risk of dementia, heart disease, kidney disease, mental health problems, fatigue, and bone loss. Scientists think HbA1c levels might also impact a person’s lifespan. Both above and below normal levels have been linked with increased mortality, but it’s still too early to say why or to what extent. Keeping your levels in the normal range is the best step you can take to lower your overall risk of health problems.
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