Skip to content
SearchProgress
Display

Display

Theme
Density
Text size

Sign in

Add your earlier progress to your account?

Study progress is waiting to be saved

HbA1c and ketones

14 min

  • Recognize when red-cell changes make an HbA1c disagree with the glucose history
  • Choose a ketone test that detects beta-hydroxybutyrate in suspected DKA

Read the full reference

Try first

Try first

A patient with hereditary spherocytosis and an active hemolytic anemia has diabetes. Home glucose readings average about 180 mg/dL. The HbA1c reads 5.4%, and the method shows no hemoglobin variant. What explains the gap?

The next section explains it.

Right. The next section explains why.

The next section explains it.

The next section explains it.

Get the idea

HbA1c depends on red-cell age

Hemoglobin A1c (HbA1c) forms when glucose attaches, without an enzyme, to the N-terminal valine of the hemoglobin A beta chain. It reflects glycemia over roughly the previous 2 to 3 months, with recent weeks weighted more.1 The result also depends on how long the red cells have circulated:2

  • Hemolysis, recovery from blood loss and erythropoietin use leave a younger red-cell population. HbA1c then reads lower than the glucose history predicts.
  • Iron deficiency may raise HbA1c.
  • Hemoglobin variants can interfere, in a direction set by the method.

When hemoglobin A is absent, as in HbSS, HbCC and HbSC, HbA1c cannot be measured and is not reported. Fructosamine and glycated albumin reflect about the previous 15 to 30 days and do not depend on red cells.1

The estimated average glucose (eAG) puts an HbA1c into glucose units, so it can be set beside measured glucose:3

eAG (mg/dL) = 28.7 × HbA1c (%) − 46.7

A large gap between the eAG and the glucose history calls for a look at the blood count, the transfusion history and the analyzer's variant pattern.2

Measure the ketone that predominates

The liver makes three ketone bodies when fatty-acid oxidation increases. Beta-hydroxybutyrate is the main ketoacid in diabetic ketoacidosis (DKA).1

Ketone bodyShare in DKANitroprusside reactionEnzymatic blood method
Beta-hydroxybutyratePredominantNoneMeasured with beta-hydroxybutyrate dehydrogenase
AcetoacetateSmallerPurple colorNot measured
AcetoneMinorWeak, with glycine formulationsNot measured

Blood beta-hydroxybutyrate is the preferred test for diagnosing DKA and following it. The consensus criterion is beta-hydroxybutyrate of 3.0 mmol/L or higher.4 A urine nitroprusside result can look modest early in DKA. During treatment, beta-hydroxybutyrate converts to acetoacetate, so the urine result can rise while the patient recovers.4

References
  1. Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care. 2023;46(10):e151-e199. doi:10.2337/dci23-0036
  2. National Glycohemoglobin Standardization Program. Factors that interfere with HbA1c test results. Updated June 23, 2026. Accessed September 27, 2026. https://ngsp.org/factors.asp
  3. National Glycohemoglobin Standardization Program. HbA1c and estimated average glucose. Accessed September 27, 2026. https://ngsp.org/A1ceAG.asp
  4. Umpierrez GE, Davis GM, ElSayed NA, et al. Hyperglycemic crises in adults with diabetes: a consensus report. Diabetes Care. 2024;47(8):1257-1275. doi:10.2337/dci24-0032

Watch one

An adult with type 2 diabetes has an HbA1c that the clinic questions. Six fasting plasma glucose results over the past 3 months ran from 150 to 190 mg/dL, averaging 170 mg/dL. The Meniscus CX-800 measures HbA1c by ion-exchange chromatography, and the chromatogram shows no variant peak.

Does the HbA1c describe this patient's glucose history?

TestResultPreviousReference intervalFlag
HbA1c5.6 %4.0–5.6 %
Hemoglobin9.8 g/dL12.0–15.5 g/dLLow
Reticulocytes6.5 %0.5–2.5 %High
Lactate dehydrogenase410 U/L120–246 U/LHigh
Haptoglobin<10 mg/dL30–200 mg/dLLow

Specimen: H 10, L 15, I 2. EDTA whole blood for HbA1c and the blood count; serum for LDH and haptoglobin

  1. Convert the HbA1c: eAG = 28.7 × 5.6 − 46.7 = 114 mg/dL. The measured glucose results average 170 mg/dL.

    The eAG puts the HbA1c into glucose units, so the two can be compared directly.

  2. Check the chromatogram: no variant peak, so an analytic interference from a variant is unlikely.

    A variant can shift the result in a direction set by the method, so the analyzer's own pattern comes next.

  3. Read the blood count: hemoglobin 9.8 g/dL with reticulocytes at 6.5% means many young cells.

    HbA1c builds up over each red cell's life, so a young red-cell population carries less of it.

  4. Read the hemolysis markers: a high lactate dehydrogenase and a haptoglobin below 10 mg/dL point to red cells destroyed early.

    These results show why the cells are young.

  5. Report the HbA1c with your procedure's comment on shortened red-cell survival, naming glucose results or fructosamine as the better measure.

    The assay measured the cells in the tube correctly, and the reader needs the reason the value runs low.

The HbA1c of 5.6% (eAG 114 mg/dL) reads low for a glucose history averaging 170 mg/dL, because hemolysis has shortened red-cell survival.

Your turn

Problem 1 of 3

How does shortened erythrocyte survival usually affect HbA1c relative to the same glycemic exposure?

Incorrect. Younger cells have had less time in circulation, so they carry less glycation.

Incorrect. A technically accurate assay still measures a cell population whose exposure time has changed.

Correct. Hemolysis, recent blood loss, and erythropoietin use leave a younger red-cell population, so HbA1c reads lower than the glucose history predicts.

Hint
  1. Glucose attaches to hemoglobin steadily through each red cell's life.
  2. Ask how long the cells in the specimen have been circulating when survival is short.

Review HbA1c and other glycated proteins

Problem 2 of 3

Which measurement directly assesses the predominant ketoacid in diabetic ketoacidosis (DKA)?

Correct. Beta-hydroxybutyrate predominates in DKA, and enzymatic methods using beta-hydroxybutyrate dehydrogenase quantify it in blood.

Incorrect. Nitroprusside reacts with acetoacetate and, in glycine formulations, weakly with acetone. Beta-hydroxybutyrate gives no reaction.

Incorrect. The anion gap reflects unmeasured anions indirectly and gives no beta-hydroxybutyrate concentration. Mixed acid-base disorders and hyperchloremic acidosis also limit it.

Hint
  1. Start with the ketone body that predominates in DKA.
  2. Ask which ketone bodies the nitroprusside reaction can see.

Review Ketones and hyperglycemic crises

Problem 3 of 3

A patient treated for DKA is followed with two tests. At admission, blood beta-hydroxybutyrate is 6.2 mmol/L and urine nitroprusside ketones are 1+. Eight hours into treatment, beta-hydroxybutyrate is 1.4 mmol/L and urine ketones are 3+. Which result shows the course of the ketoacidosis?

Nitroprusside sees acetoacetate and misses beta-hydroxybutyrate. As beta-hydroxybutyrate converts to acetoacetate during recovery, the urine result rises.

Read urine nitroprusside as total ketones in DKA

Nitroprusside reacts with acetoacetate and weakly with acetone. It does not react with beta-hydroxybutyrate, the main ketoacid in diabetic ketoacidosis (DKA). Early urine results can look modest and then rise during recovery as beta-hydroxybutyrate converts to acetoacetate, so the test misstates both severity and trend.

The two tests measure different ketone bodies. During recovery they are expected to move apart.

Blood beta-hydroxybutyrate measures the main ketoacid directly, and it fell from 6.2 to 1.4 mmol/L. The urine rise comes from beta-hydroxybutyrate converting to acetoacetate.

Review Ketones and hyperglycemic crises

Use it

  • A 34-year-old woman with sickle cell disease and type 2 diabetes, MRN 5820394, has an HbA1c ordered at a clinic visit.
  • The Meniscus CX-800 measures HbA1c by ion-exchange chromatography.
  • The chromatogram shows Hb S about 88%, Hb F 9% and Hb A2 3%, with no Hb A peak.
  • The analyzer gives no HbA1c value and flags a variant.
  • The clinic calls and asks the laboratory to run the HbA1c on another method.
Decision 1 of 3

Why can this specimen give no HbA1c that describes the patient's glycemia?

HbA1c is glycated hemoglobin A. This specimen has no hemoglobin A, so no method can find it.

Hb F can interfere in some methods. The deciding finding here is the missing Hb A peak.

HbA1c is formed on hemoglobin A, which this specimen lacks. Sickled cells also circulate for a short time, so glycation on any hemoglobin would understate the glucose history.

Review HbA1c and other glycated proteins

Decision 2 of 3

What do you report?

The comment tells the clinic why no value appears and which tests can stand in.

Any value from these cells would read low for the glucose history, because the cells circulate for a short time. A number would make glucose control look better than it is.

Read a low HbA1c as good control despite hemolysis

Hemolysis, recent blood loss, and erythropoietin use lower the average age of circulating red cells, so HbA1c reads lower than the glucose history predicts. Iron deficiency may raise it. Accepting the low value makes glucose control look better than it is and misses the red-cell cause of the discrepancy.

A new specimen has the same hemoglobin pattern and gives the same result.

No HbA1c peak exists to estimate from, and any made-up value would reach the chart as a real result.

Review HbA1c and other glycated proteins

Decision 3 of 3

The clinic asks which test can follow her glucose control. Which marker does not depend on red cells?

The eAG comes from an HbA1c, so it carries the same red-cell problem.

Fructosamine measures glycated serum protein over about the previous 15 to 30 days. Protein loss and albumin turnover still affect it.

Transfusion mixes donor cells into the specimen and changes the relationship between HbA1c and glycemia.

Review HbA1c and other glycated proteins

The clue that settled this case is the missing Hb A peak. HbA1c is formed on hemoglobin A, so a specimen without it has no HbA1c to report. The comment names the tests that can stand in.

Keep

Sources checked