Download Diabetes and Chronic Liver Disease: Etiology

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A R T I C L E
Diabetes and Chronic Liver Disease:
Etiology and Pitfalls in Monitoring
Mihaela C. Blendea, MD, PhD, Michael J. Thompson, MD, and Samir Malkani, MD
T
he liver is one of the major
targets for insulin and its counterregulatory hormones, such
as glucagon. Chronic liver disease
(CLD) is often associated with glucose intolerance and diabetes. CLD
is very prevalent in the general U.S.
population and includes 2% of adult
Americans (5.3 million) infected with
hepatitis B or C1 and an estimated
31% or more with non-alcoholic fatty
liver disease (NAFLD).2
The population of Americans
with CLD continues to expand
because of the epidemics of obesity
and diabetes. In some subpopulations such as the morbidly obese, the
prevalence of NAFLD is as high as
88%.3 The association of NAFLD
with concurrent diabetes increases
general mortality.4
Liver cirrhosis from alcohol
abuse is another important cause
of CLD.5,6 Genetic conditions such
as hemochromatosis (HC), cystic
fibrosis, and sclerosing cholangitis
are less frequent causes of CLD.
Their prevalence is populationbased; for HC, the homozygous
state prevalence is 0.6–1% in whites.7
Individuals with HC have an odds
ratio for diabetes as high as 5.4 compared to control subjects.8
Assessing glucose control using
A1C or fructosamine (FA) testing
in CLD has significant limitations.
These limitations must be clearly
understood to avoid misinterpretation of the results. Ordering these
tests should sometimes be avoided
CLINICAL DIABETES • Volume 28, Number 4, 2010
altogether in patients with a high
likelihood of falsely low results.
Relationship Between CLD
and Diabetes
The presence of CLD is associated
with significant impairment in glucose homeostasis. Glucose intolerance
is seen in up to 80% of patients with
CLD, and frank diabetes is present in
30–60%.9,10 Depending on its etiology, CLD has a significant impact on
hepatic glucose metabolism.
One of the common causes of
CLD is chronic hepatitis C. Chronic
hepatitis C is accompanied by
insulin resistance, which causes
impaired glucose tolerance. Multiple
mechanisms have been implicated,
including fat accumulation in hepatocytes, increased insulin resistance
secondary to increased tumor
necrosis factor (TNF)-α, and direct
or autoimmune damage to β-cells by
the virus.11
In a study of 229 Japanese
patients with hepatitis C (27.6% of
whom had cirrhosis and 8.9% had
chronic active hepatitis), 17.5% had
IN BRIEF
Patients with chronic liver disease
have a high prevalence of glucose
intolerance and diabetes because
of the presence of insulin resistance
and β-cell dysfunction. A1C levels
in these individuals are frequently
falsely low, limiting the utility of
A1C measurement as a diagnostic
test and monitoring tool.
diabetes compared to 5.3% in the
control population. Their average
BMI was normal at 22.4 kg/m2, and
only 10% of the patients had a family
history of diabetes compared to 40%
of control patients with diabetes.12
Different hepatitis C virus (HCV)
genotypes seem to have different
potential for interfering with glucose
metabolism. In vitro studies reveal
that genotype 1 and 3 HCV interfere
with insulin signaling.13 Clinically, in
nonobese, nondiabetic adults infected
with genotype 1 or 2 HCV, insulin
resistance correlated significantly
with the viral load and was independent of patients’ visceral adipose
tissue area as measured by abdominal computed tomography scan.14
In patients with genotype 1
HCV, sustained responders to
interferon-ribavirin therapy showed
a significant decrease in insulin
resistance compared to the baseline insulin resistance index. Also,
the incidence of overt diabetes
was reported to be lower in cured
patients than in nonresponders to
antiviral therapy.15,16 However, other
studies did not find similar beneficial
effects of long-term viral clearance.17
The presence of diabetes is
accompanied by poor response to
antiviral medications; in a recent
study,18 only 23% of patients with
both hepatitis C and diabetes
achieved sustained viral response to
pegylated interferon and ribavirin
combination therapy compared to
46% of patients with hepatitis C but
no diabetes. Patients with concur-
139
F E A T U R E
rent diabetes also reported more side
effects to therapy. In contrast, no
clear relationship between insulin
resistance or diabetes and infection was seen with hepatitis B virus
infection.19,20
There is a strong association
between NAFLD and type 2 diabetes, and the prevalence of both
disorders is increasing related to
an increase in the prevalence of
obesity.2 Both visceral obesity and
hepatic fat correlate with insulin
resistance, which is an important
precursor to the development of
type 2 diabetes. NAFLD can be a
precursor of cirrhosis, which may
have a further impact on glucose
metabolism.
In a large study of > 800,000
patients in the Veterans Affairs
health system, a twofold higher
prevalence of NAFLD and hepatocellular carcinoma in men with
A R T I C L E
preexistent diabetes was reported
compared to control patients
without diabetes.21 The presumed
sequence of events leading to the
development of NAFLD and subsequent cirrhosis in these individuals
are increased circulating free fatty
acids induced by insulin resistance,
saturation of the hepatocytes with
VLDL cholesterol, and subsequent
increased mitochondrial oxidative
stress inducing inflammation, necrosis of hepatocytes, and increased
collagen production in the liver.10
Parameters for Monitoring
Glycemic Control
Several indicators of long-term
glucose control are available. These
indicators are glycated proteins
(hemoglobin, albumin, and total
proteins), and all are a reflection of
glucose levels as well as of the turnover rate of their substrate (Table 1).
The only test that is well standardized
and in wide use is the A1C test.
A1C testing
Glycated hemoglobin, measured by
high-performance liquid chromatography, is the gold standard for
monitoring blood glucose control
in diabetes and can now also be
used to diagnose diabetes when its
results are ≥ 6.5%.22 A1C represents
the percentage of hemoglobin that
suffers irreversible non-enzymatic
glycosylation at one or two of the
amino-terminal valine of the β-chain;
the result is known as a Schiff base.
The product of this fast, unstable process can slowly form an
irreversible ketoamine through
Amadori rearrangement.23 This
stable ketoamine form remains for
the lifespan of the red blood cell
(RBC) (~ 120 days), and its value
has been shown to be well corre-
Table 1. Methods of Monitoring Diabetes Control in Patients With CLD: Clinical Relevance and Limitations
Test
General Relevance
Limitations in CLD and Observations
A1C
Estimate of average blood glucose during
the past 3 months
Likely to be falsely low. Avoid during or after antiviral
hepatitis C therapy (hemolysis). Consider checking
hemoglobin/hematocrit, liver function tests, amd
reticulocytes in every patient with CLD and diabetes.
If there is severe anemia or high RBC turnover, expect
A1C to be inaccurate, and consider alternative parameters for monitoring.
Fructosamine
(FA)
Estimate of average blood glucose during
the past 2 weeks
Likely inaccurate in patients with dysproteinemia,
very low serum albumin levels, or proteinuria.
Glycated albumin
(GA)
Not used in general practice; overall
similar significance to FA
Similar to FA
Composite
parameters
(e.g., CLD-A1C)
An attempt to combine and then compensate for disadvantages and advantages of
different markers
Not validated in clinical practice; not studied in patients with proteinuria
Frequent selfmanagement of
blood glucose
Relevant if blood glucose is checked
several times a day at different times of the
day; downloadable glucose meter memory
readily reports blood glucose average.
Advise patients to check before and 2 hours after
meals at different times of day. Appears to be best
parameter to monitor in CLD. Easy to implement in
motivated patients. Independent of therapy.
Continuous
glucose
monitoring
Currently recommended in insulin-treated
patients, especially those with recurrent
hypoglycemia episodes
Not offered routinely; not always covered by medical insurance. Considered off-label for patients not
treated with insulin.
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Volume 28, Number 4, 2010 • CLINICAL DIABETES
F E A T U R E
lated to the mean plasma glucose
levels for this period. This has been
validated by the Diabetes Control
and Complications Trial24 and was
reevaluated in the international
A1C-Derived Average Glucose
(ADAG) study.25
A1C also correlates with the risk
for developing chronic complications of diabetes.26,27 The degree of
glycosylation is dependent on the
degree of hyperglycemia, but also on
the lifespan of the RBCs. Abnormal
hemoglobins, many of them clinically silent, interfere with and can
either falsely elevate or falsely lower
A1C measurements depending on
the testing method used.28,29
The American Diabetes
Association (ADA) current diabetes
care standards22 assume that a normal A1C is ≤ 5.6%. Individuals are
considered to be at risk for diabetes
when their A1C is between 5.7 and
6.4% and are diagnosed with diabetes when their A1C is ≥ 6.5%. ADA
also recommends A1C testing routinely in all patients with diabetes at
initial assessment and then as part of
continuing care, with a target of A1C
of < 7% for microvascular disease
prevention.22
Of note, the ADAG trial, as well
as similar earlier trials, excluded
patients with a potentially altered
relationship between A1C and average glucose values. In the ADAG
study, the presence of anemia
(hematocrit < 39% in men and < 36%
in women), reticulocytosis, history of
blood loss or transfusions, chronic
renal or liver disease, and high-dose
vitamin C or erythropoietin treatment were criteria for exclusion.25
Fructosamine and glycated albumin
Fructosamine (FA) is a term used
to describe proteins that have been
glycated, forming stable ketoamines,
by a similar nonenzymatic reaction with glucose as described for
hemoglobin.30 Measuring FA by a
CLINICAL DIABETES • Volume 28, Number 4, 2010
A R T I C L E
spectrophotometric assay may be less
expensive than measuring A1C, but
the assay may be affected by hypertriglyceridemia, hyperbilirubinemia,
hemolysis, and low serum protein
and albumin levels.31 Some authors
advocate correcting FA results for
serum albumin or protein levels, but
there is no consensus on applying this
correction.32–34 The normal range of
FA is method- and laboratory-dependent (by spectrophotometric assay, it
ranges around 160–280 μmol/l).35
In patients with stable glycemic
control, there seems to be a linear
relationship between FA and A1C.36
Currently, measuring FA is recommended in patients with abnormal
hemoglobins and in those requiring
monitoring for more recent changes
in diabetes control, such as pregnant
women with diabetes. The correlation of FA with average glucose has
not been validated as well as the
correlation of A1C with average
glucose.22
Glycated albumin (GA) has
been advocated as a more accurate
parameter compared to FA in some
subgroups, such as patients undergoing hemodialysis.37,38 It can be
expressed in absolute value (g/dl)
or as percentage of total albumin.38
Because > 50% of the measured FA
is represented by GA, the significance and limitations of this method
are similar. Albumin has a half-life
of 14–20 days—much shorter than
that of the RBC. Therefore, these
tests indicate average blood glucose
levels over a 2- to 3-week period.
Assessing A1C in CLD
Among patients with CLD, anemia,
portal hypertension, hypersplenism,
and variceal bleeding can be common complications. These factors can
contribute to longer or shorter RBC
survival39 and can lead to alteration of
the A1C. Factors such as nutritional
anemia can lead to increased RBC
survival and falsely elevated A1C
levels, whereas bleeding and hemolysis can lower RBC survival time and
falsely lower A1C values. In our clinical experience, we frequently find that
individuals with cirrhosis have A1C
levels that are much lower than their
fingerstick blood glucose measurements would suggest.
Very few studies are dedicated
to systematically evaluating the
accuracy of A1C in CLD patients. In
a screening of 20,000 measurements
of A1C, patients with a very low A1C
(below the normal range) were analyzed further. Of nine abnormally
low results, six were the result of
cirrhosis, two resulted from hematological neoplasms with anemia,
and one was due to hemoglobin F.28
In a small case series (15 patients
with compensated cirrhosis and 20
patients with chronic hepatitis), 40%
of cirrhotic patients with diabetes
had A1C levels below reference
range for patients without diabetes,
whereas FA was elevated in onethird of the patients and normal for
the others.40
Anemia is frequently present
in CLD. Occasionally, autoimmune hepatitis can be associated
with hemolytic anemia,41,42 but
hypersplenism is more frequent as
a cause of reduced RBC survival.
Iron deficiency, vitamin B12 and
folate deficiency anemia (often seen
in alcoholism or malnutrition), and
anemia of chronic disease are other
common causes of anemia.
Theoretically, RBC lifespan is
longer in nutrient-deficiency anemia,
which would lead to an elevation in
A1C. However, studies in patients
without diabetes who have iron
deficiency have reported a significant
decrease in baseline A1C of 1.2–1.3%
once iron deficiency is corrected.43,44
In a recently published study based
on data from the National Health
and Nutrition Examination Survey,45
iron deficiency was associated with a
shift in A1C distribution from < 5.5
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F E A T U R E
to ≥ 5.5% in > 6,600 adult women
without diabetes.
In late pregnancy, women without
diabetes who had a drop in ferritin,
transferase, and mean corpuscular hemoglobin tended to have an
increase of A1C unrelated to glucose
levels or GA concentration.46 Similar
findings were recently reported in
pregnant women with diabetes.47
Reports in children with type 1
diabetes have also found a decrease
in A1C with iron repletion independent of blood glucose control.44 In
contrast, some studies in children
without diabetes have failed to
replicate a difference between irondeficient and iron-replete subjects.48
The clinical significance of these
findings remains to be studied.
Most likely, stringent physiological
mechanisms are in place to limit the
lifespan of older RBCs; therefore,
the increase in A1C resulting from
iron or vitamin deficiency should be
minimal. Some studies suggest that
the decrease in A1C is limited to the
“active phase” of recovery from iron
or vitamin deficiency when RBC
turnover is increased.49
Measuring FA or GA in CLD
FA and GA are parameters of diabetes
control that are less standardized and
less frequently used. They can potentially be inaccurate in CLD as well. It
is known that the half-life of albumin is
significantly increased in liver disease
from a normal half-life of 10.5 days to
11.3 days in chronic hepatitis and up to
15.9 days in cirrhosis,50 mainly through
decreased degradation induced by the
hypoalbuminemia itself.51
Albumin levels can correlate
with liver injury but not with the
activity of the underlying disease
by histology.50 Other factors, such
as protein-losing gastroenteropathy
related to portal hypertension52 or
the presence of nephropathy, can
contribute to hypoalbuminemia and
affect albumin turnover. The extent
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A R T I C L E
of glycation seems to be dependent
on the plasma albumin concentrations;32 therefore, opposing trends
can skew FA/GA in different directions, making interpretation of the
results quite difficult.
In an attempt to take advantage
of albumin and hemoglobin turnover
being altered in opposite directions
by liver disease, a novel parameter
was recently proposed.53 “CLDA1C” is a conventional parameter
defined as [A1C + GA/3]/2, where
GA is expressed as the percentage
of glycated albumin out of the total
albumin. The authors studied 82
CLD patients (including 24 patients
with diabetes) and found that CLDA1C was well correlated to the A1C
as calculated from monitoring blood
glucose seven times a day. CLD-A1C
was independent of liver function
estimated by cholinesterase levels,
platelet count, or albumin levels.
Patients with renal disease were
excluded from this study. Larger
population data are needed to validate the use of new parameters such
as CLD-A1C.
Impact of Medications on Monitoring
Special attention should be given to
CLD patients on certain medications
that can significantly alter the erythrocyte lifespan. Hemolysis is a known
side effect of ribavirin therapy for
hepatitis C. Severe anemia develops
in ~ 10% of treated patients and is
likely related to extensive ribavarin
accumulation in erythrocytes followed by inhibition of intracellular
energy metabolism and oxidative
membrane damage. This leads to an
accelerated extravascular hemolysis
by the reticulo-endothelial system.54
Ribavirin can decrease the erythrocyte lifespan from 120 to 40 days.55
In a study of 20 patients with
chronic hepatitis without a history of
glucose intolerance or diabetes, 20%
had A1C results < 4.5%. In contrast,
their FA levels were normal. In the
subgroup treated with ribavirin, half
of A1C results were below the nondiabetic reference.40 A case report56 has
described an individual with CLD
treated with ribavarin, who had a
dramatic decrease in the A1C from 11
to 4.9 and then 4.4%. This decrease
was related to ribavirin adverse
effects rather than to improvements
in blood glucose control.
Other Options for Monitoring Blood
Glucose in CLD
Self-monitoring of blood glucose
Checking fingerstick blood glucose
frequently and at different times of
the day allows an accurate estimate
of the real blood glucose control in all
patients with diabetes. This strategy
of monitoring might be of particular
interest in CLD patients, given the
drawbacks of the standard parameters discussed above. Downloading
glucose readings from the glucose
meter memory is particularly useful because computer programs can
report an average blood glucose that
can be compared to measured A1C
(and the derivate estimated average glucose). Thus, any discrepancy
between monitoring parameters can
be readily evaluated.
Continuous glucose monitoring
(CGM) with interstitial sensors is
another option to be considered. At
present, CGM is considered to be “a
useful supplemental tool for adult
patients on insulin that present with
hypoglycemia unawareness and/or
frequent hypoglycemic episodes.”22
CLD patients—especially those
with cirrhosis—have poor hepatic
glycogen reserve and therefore are at
risk for severe hypoglycemic events.57
Moreover, insulin is a preferred
therapy in cirrhotic patients with
diabetes because most oral hypoglycemic agents have some potential for
liver toxicity58 or altered metabolism
in CLD. Thus, use of CGM should be
considered in selected cases and espe-
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F E A T U R E
cially in insulin-treated patients with
recurrent hypoglycemic episodes.
Conclusions
Measuring glycemic control can be
challenging in patients with CLD. A
summary of the different measures
available and their strengths and
limitations is shown in Table 1.
Measuring A1C is unreliable in
patients with cirrhosis and in many
patients with chronic hepatitis. Any
increase in hemoglobin turnover
secondary to gastrointestinal bleeding, hemolysis by hypersplenism, or
medications can grossly underestimate glucose levels and thus give
false reassurance to patients and
physicians regarding the risk for
developing diabetes complications.
In view of current ADA recommendations, it may also delay diagnosis
of diabetes if A1C is used for screening in this group of patients.
Because A1C is currently being
used as both a diagnostic test and
a parameter of good practice in
monitoring glucose control in diabetic patients, it is easy to overlook
the fact that its relationship with
blood glucose has been established
in patients without anemia, chronic
kidney or liver disease, or therapies
that can interfere with results. When
measuring A1C in patients with
CLD, physicians should be fully
aware of its limitations. If A1C is
measured in these patients, levels
and dynamics of total hemoglobin, reticulocytes, medication use,
and liver function tests should be
reviewed for better interpretation of
the results. FA or GA can be used as
secondary parameters of monitoring blood glucose control, but they
also have limitations that must be
understood.
Reviewing actual blood glucose meter readings, provided that
patients check their blood glucose
frequently and at different times during the day, reflects the true degree
CLINICAL DIABETES • Volume 28, Number 4, 2010
A R T I C L E
of glucose control more accurately.
CGM devices have the potential of
measuring glycemic excursions in
patients with CLD and should be
considered in patients who use insulin, especially if they present with
recurrent hypoglycemia.
In conclusion, an individualized
approach tailored to the different
stages of liver disease should be considered when monitoring diabetes in
these challenging patients.
REFERENCES
1
Institute of Medcine: Hepatitis and liver
cancer: a national strategy for prevention
and control of hepatitis B and C [consensus
report]. Available online from www.iom.edu/
Reports/2010/Hepatitis-and-Liver-CancerA-National-Strategy-for-Prevention-andControl-of-Hepatitis-B-and-C.aspx. Accessed
3 May 2010
2
Browning JD, Szczepaniak LS, Dobbins
R, Nuremberg P, Horton JD, Cohen JC,
Grundy SM, Hobbs HH: Prevalence of
hepatic steatosis in an urban population
in the United States: impact of ethnicity.
Hepatology 40:1387–1395, 2004
3
Angulo P: GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol
Ther 25:883–889, 2007
4
Adams LA, Harmsen S, St Sauver
JL, Charatcharoenwitthaya P, Enders FB,
Therneau T, Angulo P: Nonalcoholic fatty
liver disease increases risk of death among
patients with diabetes: a community-based
cohort study. Am J Gastroenterol 105:1567–
1573, 2010
5
Hasin DS, Stinson FS, Ogburn E, Grant
BF: Prevalence, correlates, disability, and
comorbidity of DSM-IV alcohol abuse and
dependence in the United States: results
from the National Epidemiologic Survey on
Alcohol and Related Conditions. Arch Gen
Psychiatry 64:830–842, 2007
6
National Institute of Alcohol Abuse and
Alcoholism: Age-specific and age-adjusted
death rates for cirrhosis with and without
mention of alcohol, United States, 1970–2005.
Available online from http://www.niaaa.
nih.gov/Resources/DatabaseResources/
QuickFacts/Liver/cirmrt3b.htm. Accessed 12
May 2010
7
Edwards CQ, Griffen LM, Goldgar
D, Drummond C, Skolnick MH, Kushner
JP: Prevalence of hemochromatosis among
11,065 presumably healthy blood donors. N
Engl J Med 318:1355–1362, 1988
10
García-Compean D, Jaquez-Quintana
JO, Maldonado-Garza H: Hepatogenous diabetes: current views of an ancient problem.
Ann Hepatol 8:13–20, 2009
11
Antonelli A, Ferri C, Ferrari SM, Colaci
M, Sansonno D, Fallahi P: Endocrine manifestations of hepatitis C virus infection. Nat
Clin Pract Endocrinol Metab 5:26–34, 2009
12
Kuriyama S, Miwa Y, Fukushima H,
Nakamura H, Toda K, Shiraki M, Nagaki
M, Yamamoto M, Tomita E, Moriwaki H:
Prevalence of diabetes and incidence of
angiopathy in patients with chronic viral liver
disease. J Clin Biochem Nutr 40:116–122, 2007
13
Banerjee S, Saito K, Ait-Goughoulte M,
Meyer K, Ray RB, Ray R: Hepatitis C virus
core protein upregulates serine phosphorylation of insulin receptor substrate-1 and
impairs the downstream akt/protein kinase
B signaling pathway for insulin resistance. J
Virol 82:2606–2612, 2008
14
Yoneda M, Saito S, Ikeda T, Fujita
K, Mawatari H, Kirikoshi H, Inamori M,
Nozaki Y, Akiyama T, Takahashi H, Abe Y,
Kubota K, Iwasaki T, Terauchi Y, Togo S,
Nakajima A: Hepatitis C virus directly associates with insulin resistance independent of
the visceral fat area in nonobese and nondiabetic patients. J Viral Hepat 14:600–607, 2007
15
Romero-Gómez M, Del Mar Viloria
M, Andrade RJ, Salmerón J, Diago M,
Fernández-Rodríguez CM, Corpas R, Cruz
M, Grande L, Vázquez L, Muñoz-De-Rueda
P, López-Serrano P, Gila A, Gutiérrez
ML, Pérez C, Ruiz-Extremera A, Suárez
E, Castillo J: Insulin resistance impairs
sustained response rate to peginterferon
plus ribavirin in chronic hepatitis C patients.
Gastroenterology 128:636–641, 2005
16
Simó R, Lecube A, Genescà J, Esteban
JI, Hernández C: Sustained virological
response correlates with reduction in the
incidence of glucose abnormalities in patients
with chronic hepatitis C virus infection.
Diabetes Care 29:2462–2466, 2006
17
Giordanino C, Bugianesi E, Smedile A,
Ciancio A, Abate ML, Olivero A, Pellicano
R, Cassader M, Gambino R, Bo S, Ciccone
G, Rizzetto M, Saracco G: Incidence of type
2 diabetes mellitus and glucose abnormalities
in patients with chronic hepatitis C infection
by response to treatment: results of a cohort
study. Am J Gastroenterol 103:2481–2487,
2008
18
Elgouhari HM, Zein CO, Hanouneh I,
Feldstein AE, Zein NN: Diabetes mellitus is
associated with impaired response to antiviral therapy in chronic hepatitis C infection.
Dig Dis Sci 54:2699–2705, 2009
19
Kumar M, Choudhury A, Manglik N,
Hissar S, Rastogi A, Sakhuja P, Sarin SK:
Insulin resistance in chronic hepatitis B virus
infection. Am J Gastroenterol 104:76–82, 2009
Crooks CJ, West J, Solaymani-Dodaran
M, Card TR: The epidemiology of haemochromatosis: a population-based study.
Aliment Pharmacol Ther 29:183–192, 2009
20
Wang CC, Hsu CS, Liu CJ, Kao JH,
Chen DS: Association of chronic hepatitis
B virus infection with insulin resistance and
hepatic steatosis. J Gastroenterol Hepatol
23:779–782, 2008
9
Petrides AS: Liver disease and diabetes
mellitus. Diabetes Rev 2:1–18, 1994
21
El-Serag HB, Tran T, Everhart JE:
Diabetes increases the risk of chronic liver
8
143
F E A T U R E
A R T I C L E
disease and hepatocellular carcinoma.
Gastroenterology 126:460–468, 2004
control in diabetic patients with CKD Stages
3 and 4. Am J Kidney Dis 55:867–874, 2010
pregnancy in diabetic women. Diabetes Care
33:509–511, 2010
22
American Diabetes Association:
Standards of medical care in diabetes—2010.
Diabetes Care 33 (Suppl. 1):S11–S61, 2010
36
Jerntorp P, Sundkvist G, Fex G,
Jeppsson JO: Clinical utility of serum,
fructosamine in diabetes mellitus compared
with hemoglobin A1C. Clin Chim Acta
175:135–142, 1987
48
Aslan D, Gursel T: The usefulness
of glycosylated hemoglobin (HbA1c) in
discriminating between iron deficiency
and thalassemia. Pediatr Hematol Oncol
23:307–315, 2006
37
Paroni R, Ceriotti F, Galanello R,
Battista Leoni G, Panico A, Scurati E,
Paleari R, Chemello L, Quaino V, Scaldaferri
L, Lapolla A, Mosca A: Performance characteristics and clinical utility of an enzymatic
method for the measurement of glycated
albumin in plasma. Clin Biochem 40:1398–
1405, 2007
49
Gram-Hansen P, Eriksen J, MouritsAndersen T, Olesen L: Glycosylated
haemoglobin (HbA1c) in iron- and vitamin
B12 deficiency. J Intern Med 227:133–136, 1990
23
Hodge JE: The Amadori rearrangement.
Adu Carbohydr Chem 10:169–205, 1955
24
Rohlfing CL, Wiedmeyer HM, Little
RR, England JD, Tennill A, Goldstein DE:
Defining the relationship between plasma
glucose and HbA1c: analysis of glucose
profiles and HbA1c in the Diabetes Control
and Complications Trial. Diabetes Care
25:275–278, 2002
25
Nathan DM, Kuenen J, Borg R, Zheng
H, Schoenfeld D, Heine RJ; A1C-Derived
Average Glucose Study Group: Translating
the A1C assay into estimated average glucose
values. Diabetes Care 31:1473–1478, 2008
26
DCCT Research Group: The effect
of intensive treatment of diabetes on the
development and progression of long-term
complications in insulin-dependent diabetes
mellitus. N Engl J Med 329:977–986, 1993
27
Stratton IM, Adler AI, Neil HA,
Matthews DR, Manley SE, Cull CA, Hadden
D, Turner RC, Holman RR: Association of
glycaemia with macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational
study. BMJ 321:405–412, 2000
28
Schnedl WJ, Lahousen T, Krause R,
Wallner SJ, Piswanger-Soelkner C, Lipp RW:
Evaluation of conditions associated with glycated hemoglobin values below the reference
range. Clin Lab 53:179–181, 2008
29
Molinaro RJ: Targeting HbA1c:
standardization and clinical laboratory
measurement. MLO Med Lab Obs 40:10–14,
16–19, 2008
30
Johnson RN, Metcalf PA, Baker JR:
Fructosamine: a new approach to the estimation of serum glycosylprotein: an index of
diabetic control. Clin Chim Acta 127:87–95,
1983
31
Goldstein DE, Little RR, Lorenz RA,
Malone JI, Nathan DM, Peterson CM;
American Diabetes Association: Tests of glycemia in diabetes. Diabetes Care 27 (Suppl.
1):S91–S93, 2004
32
Schleicher ED, Olgemöller B,
Wiedenmann E, Gerbitz KD: Specific glycation of albumin depends on its half-life. Clin
Chem 39:625–628, 1993
33
Hill RP, Hmdle EJ, Howey JEA,
Lemon M, Lloyd DR: Recommendations for
adopting standard conditions and analytical procedures in the measurement of serum
fructosamine concentration. Ann Clin
Biochem 27:413–424, 1990
34
MacDonald D, Pang CP, Cockram CS,
Swaminathan R: Fructosamine measurements in serum and plasma. Clin Chim Acta
168:247–252, 1987
35
Chen HS, Wu TE, Lin HD, Jap TS,
Hsiao LC, Lee SH, Lin SH: Hemoglobin
A1C and fructosamine for assessing glycemic
144
38
Inaba M, Okuno S, Kumeda Y, Yamada
S, Imanishi Y, Tabata T, Okamura M, Okada
S, Yamakawa T, Ishimura E, Nishizawa
Y; Osaka CKD Expert Research Group:
Glycated albumin is a better glycemic indicator than glycated hemoglobin values in
hemodialysis patients with diabetes: effect of
anemia and erythropoietin injection. J Am
Soc Nephrol 18:896–903, 2007
39
Morse EE: Mechanisms of hemolysis in
liver disease. Ann Clin Lab Sci 20:169–174,
1990
40
Lahousen T, Hegenbarth K, Ille R,
Lipp RW, Krause R, Little RR, Schnedl WJ:
Determination of glycated hemoglobin in
patients with advanced liver disease. World J
Gastroenterol 10:2284–2286, 2004
41
Gurudu SR, Mittal SK, Shaber
M, Gamboa E, Michael S, Sigal LH:
Autoimmune hepatitis associated with
autoimmune hemolytic anemia and anticardiolipin antibody syndrome. Dig Dis Sci
45:1878–1880, 2000
42
Kondo H, Kajii E, Oyamada T,
Kasahara Y: Direct antiglobulin test negative
autoimmune hemolytic anemia associated
with autoimmune hepatitis. Int J Hematol
68:439–443, 1998
43
Coban E, Ozdogan M, Timuragaoglu A:
Effect of iron deficiency anemia on the levels
of hemoglobin A1C in nondiabetic patients.
Acta Haematol 112:126–128, 2004
44
Tarim O, Küçükerdogan A, Günay U,
Eralp O, Ercan I: Effects of iron deficiency
anemia on hemoglobin A1C in type 1 diabetes mellitus. Pediatr Int 41:357–362, 1999
45
Kim C, McKeever BK, Herman WH,
Beckles G: Association between iron deficiency and A1C levels among adults without
diabetes in the National Health and Nutrition
Examination Survey, 1999–2006. Diabetes
Care 33:780–785, 2010
46
Hashimoto K, Noguchi S, Morimoto
Y, Hamada S, Wasada K, Imai S, Murata Y,
Kasayama S, Koga M: A1C but not serum
glycated albumin is elevated in late pregnancy owing to iron deficiency. Diabetes Care
31:1945–1948, 2008
47
Hashimoto K, Osugi T, Noguchi S,
Morimoto Y, Wasada K, Imai S, Waguri
M, Toyoda R, Fujita T, Kasayama S, Koga
M: A1C but not serum glycated albumin is
elevated because of iron deficiency in late
50
Takeuchi J, Takada A: Hypoproteinemia
in liver diseases. Japan J Med 7:305–307, 1968
51
Weigand K: The regulation of serum
albumin in physiological and pathological
conditions. Klin Wochenschr 55:295–305, 1977
52
Takada K, Kobayashi J, Takeuchi J:
Gastroenteric clearance of albumin in liver
cirrhosis: relative protein-losing gastroenteropathy. Digestion 3:154–164, 1970
53
Koga M, Kasayama S, Kanehara H,
Bando Y: CLD (chronic liver diseases): HbA1c
as a suitable indicator for estimation of mean
plasma glucose in patients with chronic liver
diseases. Diabetes Res Clin Pract 81:258–262,
2008
54
Russmann S, Grattagliano I, Portincasa
P, Palmieri VO, Palasciano G: Ribavirininduced anemia: mechanisms, risk factors
and related targets for future research. Curr
Med Chem 13:3351–3357, 2006
55
Krishnan SM, Dixit NM: Estimation
of red blood cell lifespan from alveolar
carbon monoxide measurements. Transl Res
154:15–17, 2009
56
Robertson M: Artificially low HbA1c
associated with treatment with ribavirin.
BMJ 336:505, 2008
57
Tolman KG, Fonseca V, Dalpiaz A,
Tan MH: Spectrum of liver disease in type
2 diabetes and management of patients with
diabetes and liver disease. Diabetes Care
30:734–743, 2007
58
McNeely M: Case study: diabetes in
a patient with cirrhosis. Clinical Diabetes
22:42–43, 2004
Mihaela C. Blendea, MD, PhD, is
an assistant professor, and Samir
Malkani, MD, is a clinical associate
professor of medicine in the University
of Massachusetts Medical Center
Department of Medicine, Division
of Endocrinology and Diabetes,
in Worcester, Mass. Michael J.
Thompson, MD, is an associate
professor of medicine in the George
Washington University Department of
Medicine, Division of Endocrinology
and Metabolism, in Washington, D.C.
Volume 28, Number 4, 2010 • CLINICAL DIABETES