Abnormal liver function tests associated with severe rhabdomyolysis

Abstract

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium, phosphate, urate and intracellular proteins such as myoglobin into the circulation, which may cause complications including acute kidney injury, electrolyte disturbance and cardiac instability. Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis. Typically, there is an increase in serum aminotransferases, namely aspartate aminotransferase and alanine aminotransferase. This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy. However, muscle can also be a source of the increased aminotransferase activity. This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association. It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases, and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury. Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury. This review also explores potential approaches to improve the accuracy of our diagnostic tools, so that excessive or unnecessary liver investigations can be avoided.

Full text

World Journal of
Gastroenterology
World J Gastroenterol 2020 March 14; 26(10): 995-1106
ISSN 1007-9327 (print)
ISSN 2219-2840 (online)
Published by Baishideng Publishing Group Inc

W J G World Journal of
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Contents Weekly Volume 26 Number 10 March 14, 2020
OPINION REVIEW
995 Global whole family based-Helicobacter pylori eradication strategy to prevent its related diseases and gastric
cancer
Ding SZ
REVIEW
1005 Role of spleen tyrosine kinase in liver diseases
Kurniawan DW, Storm G, Prakash J, Bansal R
MINIREVIEWS
1020 Abnormal liver function tests associated with severe rhabdomyolysis
Lim AKH
ORIGINAL ARTICLE
Basic Study
1029 Mesencephalic astrocyte-derived neurotrophic factor ameliorates steatosis in HepG2 cells by regulating
hepatic lipid metabolism
He M, Wang C, Long XH, Peng JJ, Liu DF, Yang GY, Jensen MD, Zhang LL
Retrospective Cohort Study
1042 Prognostic factors and predictors of postoperative adjuvant transcatheter arterial chemoembolization benefit
in patients with resected hepatocellular carcinoma
Chen MY, Juengpanich S, Hu JH, Topatana W, Cao JS, Tong CH, Lin J, Cai XJ
Retrospective Study
1056 Double-balloon endoscopic retrograde cholangiopancreatography for patients who underwent liver
operation: A retrospective study
Nishio R, Kawashima H, Nakamura M, Ohno E, Ishikawa T, Yamamura T, Maeda K, Sawada T, Tanaka H, Sakai D,
Miyahara R, Ishigami M, Hirooka Y, Fujishiro M
1067 Serum N-glycan markers for diagnosing liver fibrosis induced by hepatitis B virus
Cao X, Shang QH, Chi XL, Zhang W, Xiao HM, Sun MM, Chen G, An Y, Lv CL, Wang L, Nan YM, Chen CY, Tan ZN, Liu XE,
Zhuang H
1080 Predictors of outcomes of endoscopic balloon dilatation in strictures after esophageal atresia repair: A
retrospective study
Dai DL, Zhang CX, Zou YG, Yang QH, Zou Y, Wen FQ
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Contents World Journal of Gastroenterology
Volume 26 Number 10 March 14, 2020
Prospective Study
1088 Technetium-99m-labeled macroaggregated albumin lung perfusion scan for diagnosis of hepatopulmonary
syndrome: A prospective study comparing brain uptake and whole-body uptake
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META-ANALYSIS
1098 Is aggressive intravenous fluid resuscitation beneficial in acute pancreatitis? A meta-analysis of randomized
control trials and cohort studies
Gad MM, Simons-Linares CR
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Contents World Journal of Gastroenterology
Volume 26 Number 10 March 14, 2020
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Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2020 March 14; 26(10): 1020-1028
DOI: 10.3748/wjg.v26.i10.1020 ISSN 1007-9327 (print) ISSN 2219-2840 (online)
MINIREVIEWS
Abnormal liver function tests associated with severe
rhabdomyolysis
Andy KH Lim
ORCID number: Andy KH Lim
(0000-0001-7816-4724).
Author contributions: Lim AKH
conceptualized and wrote the
paper.
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have no potential conflict of
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work.
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Manuscript source: Invited
manuscript
Received: October 28, 2019
Peer-review started: October 28,
2019
First decision: December 12, 2019
Revised: January 6, 2020
Accepted: March 9, 2020
Article in press: March 9, 2020
Published online: March 14, 2020
P-Reviewer: Shimizu Y
S-Editor: Wang JL
L-Editor: A
E-Editor: Ma YJ
Andy KH Lim, Department of General Medicine, Monash Health, Clayton VIC 3168, Australia
Andy KH Lim, Department of Medicine, School of Clinical Sciences, Monash University,
Clayton VIC 3168, Australia
Corresponding author: Andy KH Lim, MBBS, FRACP, MMed(ClinEpi), PhD, Senior
Lecturer, Staff Physician, Department of General Medicine, Monash Health, and Department
of Medicine, School of Clinical Sciences, Monash University, 246 Clayton Road, Clayton VIC
3168, Australia. andy.lim@monash.edu
Abstract
Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular
constituents such as potassium, phosphate, urate and intracellular proteins such
as myoglobin into the circulation, which may cause complications including
acute kidney injury, electrolyte disturbance and cardiac instability. Abnormal
liver function tests are frequently observed in cases of severe rhabdomyolysis.
Typically, there is an increase in serum aminotransferases, namely aspartate
aminotransferase and alanine aminotransferase. This raises the question of liver
injury and often triggers a pathway of investigation which may lead to a liver
biopsy. However, muscle can also be a source of the increased aminotransferase
activity. This review discusses the dilemma of finding abnormal liver function
tests in the setting of muscle injury and the potential implications of such an
association. It delves into some of the clinical and experimental evidence for
correlating muscle injury to raised aminotransferases, and discusses
pathophysiological mechanisms such as oxidative stress which may cause actual
liver injury. Serum aminotransferases lack tissue specificity to allow clinicians to
distinguish primary liver injury from muscle injury. This review also explores
potential approaches to improve the accuracy of our diagnostic tools, so that
excessive or unnecessary liver investigations can be avoided.
Key words: Rhabdomyolysis; Muscle; Creatine kinase; Liver function tests; Alanine
aminotransferase; Aspartate aminotransferase; Aminotransferases
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: There is observational and experimental data demonstrating that serum alanine
and aspartate aminotransferases can be elevated in patients with rhabdomyolysis due to
muscle release of these enzymes, and cause confusion with liver disease. Clinicians
should firstly appreciate this association exists and secondly, understand the typical
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pattern and trajectory of the levels of creatine kinase and aminotransferases in the setting
of rhabdomyolysis. An atypical trajectory, concurrently elevated bilirubin or γ-glutamyl
transferase, or serum alanine aminotransferase levels above 800 U/L are inconsistent
with isolated muscle injury as the cause of the elevated aminotransferases, and further
investigation for liver disease may be warranted.
Citation: Lim AKH. Abnormal liver function tests associated with severe rhabdomyolysis.
World J Gastroenterol 2020; 26(10): 1020-1028
URL: https://www.wjgnet.com/1007-9327/full/v26/i10/1020.htm
DOI: https://dx.doi.org/10.3748/wjg.v26.i10.1020
INTRODUCTION
Rhabdomyolysis is defined as muscle injury which is significant enough to result in
release of potentially toxic cellular contents into the circulation. These cellular
contents include metabolites such as potassium, phosphate and urate, enzymes such
as creatine kinase (CK) and lactate dehydrogenase (LDH), and intracellular proteins
such as myoglobin[1]. Serum CK is used to diagnose rhabdomyolysis and most studies
use a cut-off of five times the upper limit of normal, or equivalent to 1000 U/L[1].
Symptoms of rhabdomyolysis are typically myalgias, weakness and dark urine due to
myoglobinuria. Severe cases may result in compartment syndrome, electrolyte
disturbance which may cause arrhythmia or cardiac instability, acute kidney injury
(AKI) and disseminated intravascular coagulation[1-4]. Rhabdomyolysis was first
recognised in war injuries and crush syndrome but many causes are now appreciated.
The discussion of causes and treatment are beyond the scope of this review and are
covered elsewhere[1-4]. The main aim of this review is to discuss the association
between rhabdomyolysis and abnormal liver function tests.
ABNORMAL LIVER FUNCTION IN RHABDOMYOLYSIS
The usual liver panel tests include bilirubin, alkaline phosphatase (ALP), aspartate
aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transferase
(GGT). The aminotransferases (AST and ALT) are involved in liver gluconeogenesis
and are good biomarkers for liver cell injury. AST is present in cytosolic and
mitochondrial isoenzymes and is found in the liver, cardiac muscle, skeletal muscle,
kidneys, brain, pancreas, lungs, leucocytes, and red cells. It is less sensitive and
specific for the liver. On the other hand, ALT is a cytosolic enzyme which is more
specific to the liver due to the high concentration in liver tissue. ALT is also found in
skeletal muscle but in much lower concentrations[5].
Abnormal liver function tests are frequently observed in patients with severe
rhabdomyolysis but compared to electrolyte derangements, this is a much less
appreciated phenomenon that is still shrouded in uncertainty. An example of such a
case is shown in Figure 1.
The quandary facing the clinician is determining the source of the elevated
aminotransaminases in rhabdomyolysis, as the difference in aminotransferases
between liver and muscle is quantitative rather than qualitative. At the first instance,
the other liver markers may be useful for differentiating a muscle or liver source of
AST or ALT[6]. GGT is not found in muscle and would suggest liver injury if elevated.
Similarly, elevation in bilirubin would not be expected in isolated muscle injury. The
association between serum CK and liver biochemistry is demonstrated in Figure 2.
The uncertainty arises in patients with elevated CK and isolated increase in
aminotransferases. Is it liver, muscle or both?
POTENTIAL IMPLICATIONS
Why is the association between rhabdomyolysis and abnormal liver function tests
important to recognise? Abnormalities of liver function tests are relatively common
and liver injury is frequently associated with many commonly used medications. On
the other hand, rhabdomyolysis is uncommon, and symptoms may be relatively mild.
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Figure 1
Figure 1 Case example of elevated alanine aminotransferase level in a 25 year old male admitted to hospital
with exertional rhabdomyolysis managed with intravenous normal saline for 48 h, showing the typical
concurrent rise and fall of serum creatine kinase and alanine aminotransferase levels.
Unnecessary testing or missed diagnosis
When there is no history of muscle disease or injury, clinicians may erroneously
attribute elevated aminotransferases to liver injury. Even with known
rhabdomyolysis, additional tests for liver disease (biochemistry, serology and
molecular) have mostly been negative, and 30%-50% of hepatobiliary imaging
(sonography and computed tomography) were normal with most abnormalities
consistent with hepatic steatosis[6]. Consequently, this may result in unnecessary liver
tests, including invasive tests such as a liver biopsy, which mostly reveals no
abnormalities[7]. As a corollary of over-investigating for liver disease, there could be a
failure to recognise and investigate muscle disease. For example, a 27-year old man
endured seven years of investigations for abnormal aminotransferases and had two
liver biopsies, before the identification of an elevated CK led to a final diagnosis of
muscular dystrophy[8].
Implications for clinical trials and critical medicines
The finding of abnormal liver function tests is of significant concern in clinical trials of
investigational products and may potentially see novel drug development falter. For
example, in vaccine trials, vigorous physical activity have been known to confound
results and interpretation of liver function tests, where increased CK and
aminotransferases were noted[9,10]. Recognising the association could also prevent
unnecessary avoidance of useful or critical treatments which are potentially
hepatotoxic[11].
Association with mortality
There are studies suggesting that abnormal liver function tests in patients with muscle
injury is associated with higher mortality in some clinical contexts. In critically ill
patients with rhabdomyolysis, patients who had a AST or ALT over 1000 U/L had a
higher mortality than those with levels below 1000 U/L (61% vs 15%)[12]. In another
rhabdomyolysis study, a higher CK/ALT ratio was associated with lower mortality,
even after adjusting for age, AKI and sepsis[6]. In the general population, abnormal
liver function is associated with increased all-cause mortality. Where ALT is
concerned, there is geographical variation and Asian populations seem to have a
higher risk than North American populations[13]. The reason for the association with
mortality is not clear and should be investigated.
EVIDENCE FOR MUSCLE DERIVED ALT IN
RHABDOMYOLYSIS
Is there data to demonstrate that muscle is the source of elevated aminotransferases?
If we subscribe to this theory, a few basic facts need to be demonstrated. Firstly,
aminotransferases can be localised to muscle at a cellular level. Secondly, we can
increase serum aminotransferases by inducing muscle injury. Thirdly, we can show
that the elevated aminotransferases normalise with resolution of muscle injury.
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Figure 2
Figure 2 The association between serum creatine kinase and liver biochemistry. Cross-sectional data (n = 528) show a clear association between serum
creatine kinase level as a marker of rhabdomyolysis and the serum alanine aminotransferase levels (C), but there is no correlation between serum creatine kinase and
alkaline phosphatase (A), bilirubin (B) or γ-glutamyl transferase (D) (Figure adapted from Lim et al[6]).
Ideally, we should be able to demonstrate that no other evidence of liver injury exists.
Cellular localisation
In diverse animal species, ALT, AST and LDH can be found in multiple tissues,
including kidney, liver and muscle[14,15]. Yang et al[16] used molecular methods to
quantify the distribution of ALT1 and ALT2 mRNA in rats, and showed that ALT1 is
mainly expressed (from high to low) in the intestines, liver, fat, colon, muscle and
heart. ALT2 mRNA is more limited in distribution, to liver, muscle, brain and white
adipose tissue. ALT1 is mostly intracytoplasmic while the more abundant ALT2 is
localised to mitochondria. In humans, ALT is more specific for the liver than AST but
it is known to exist in red blood cells, kidney, brain, heart and skeletal muscle[17].
However, there is paucity of data on the quantitative differences between tissues.
Wroblewski[17] reported that ALT was 10 times more abundant in the liver than
muscle. Apple and Rogers suggested that the ratio of the amount of ALT between an
equivalent weight of muscle and liver was 1:4[18]. The differences between studies may
reflect the method of measurement, and a more detailed analysis may be more
revealing.
Clinical studies of muscle injury
There are a few human studies which provided proof of concept for the association
between muscle injury and elevated aminotransferases. Pettersson et al[19] subjected 15
fit young men aged 18-45 years to a one-hour weightlifting session. They
demonstrated that AST, ALT, LDH, CK and myoglobin were significantly increased
after the activity, and it took at least 7 d to normalise, while the bilirubin, ALP and
GGT remained normal. In a study by Pal et al[20], 44 post-pubertal boys and girls
underwent intensive treadmill exercise. They also demonstrated that serum ALT and
AST increased significantly at 24 and 48 h in association with a raised CK and LDH.
The effects were more pronounce in boys compared to girls. These prospective clinical
studies provide better evidence than case reports because they were performed in
otherwise healthy individuals with normal baseline biochemistry. There is also less
risk of confounding by concurrent illness and medication use.
In a histological study, Apple and Rogers examined the serum and muscle activity
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of ALT in 30 marathon runners for acute changes. The investigators performed
gastrocnemius muscle biopsies at 9 wk and 48 h prior to the marathon, and at 24 h
after. They showed that serum ALT was significantly elevated at 24 h after the race
compared to pre-race levels. ALT levels remained elevated at 96 h. The investigators
noted that the muscle content of ALT did not significantly increase after the race and
believed that the elevated serum ALT was more likely due to hepatic release[18]. It is
difficult to support the conclusion of Apple and Rogers. They also showed that the
ALT activity per wet tissue weight of muscle was around 20% that of the liver (12 U/g
vs 50 U/g). The fallacy in their argument lies in the fact that absolute skeletal muscle
mass far exceeds liver mass, being estimated at 21 kg in women and 33 kg in men, on
average[21]. Trivial changes in one gram of muscle tissue may be significant when
amplified 20000 times.
Pattern and trajectory of CK and aminotransferases
As shown in our case example, the temporal changes in CK and ALT is fairly typical
in observational data of rhabdomyolysis as well as in human experimental data[19,22]. A
significant rise in CK is usually detectable within 24 h after the inciting injury, peaks
around 72 h, and declines over a period of 7 to 12 d. A significant rise in AST is
usually detectable at 24 h when ALT may still be in the normal range until 48 h. The
AST tends to peak around 3 to 4 d and the ALT peaks later at 4 to 5 d post injury. The
AST tends to be higher than ALT such that the AST/ALT ratio is usually greater than
one. In the case report of exertional rhabdomyolysis, the average AST/ALT ratio in
the first seven days of admission was 3.0 (range, 1.24 to 4.72)[22]. The peak AST/ALT
tends to occur at the same time as peak AST, on day 3 from onset of injury[19]. With
severe rhabdomyolysis, the aminotransferases may remain abnormal for 2 to 3 wk.
There may be a period when CK has normalised but aminotransferases remain
elevated.
Mathur et al[11] conducted an observational study of inflammatory myopathy
patients and demonstrated that abnormal serum aminotransferases follow the CK
levels. In 85 patients with inflammatory myopathy and a mean CK of over 5000 U/L,
the peak CK level was strongly correlated with the AST (r = 0.87) and ALT (r = 0.84).
At the peak CK level, the mean ± SD for the AST was 215 ± 227 U/L, and the mean ±
SD for ALT was 137 ± 137 U/L. More importantly, aminotransferases normalised in
85% of patients at the time of CK normalisation after treatment[11].
In observational studies, the timing of the inciting injury relative to presentation or
admission cannot always be accurately determined, and the biomarkers associated
with rhabdomyolysis may be either rising or falling. Treatment with intravenous
fluids often accelerates CK decline with little effect on aminotransferases, as CK is
predominantly cleared by the kidneys but ALT is cleared by the liver itself.
EVIDENCE FOR LIVER DERIVED ALT IN RHABDOMYOLYSIS
So far, we assumed aminotransferases are released from injured muscle but there may
be other mechanisms which cause liver injury. An earlier report suggested that
proteases are released after rhabdomyolysis[23]. There have been other hypotheses but
good evidence is not available. For an indirect mechanism to have a role, injured
muscles should release mediators which exert a systemic effect. The best candidate is
probably oxidative stress.
Oxidative stress and inflammation
In rats, Plotnikov et al[24] found that myoglobin released from muscle causes lipid
peroxidation of mitochondrial membranes, mitochondrial dysfunction and oxidative
stress in renal tubular cells. Oxidative stress and lipid peroxidation of fatty acids may
be responsible for increased F2-isoprostanes, which promote inflammation,
endothelial dysfunction, vasoconstriction, and apoptosis[25]. In experimental
rhabdomyolysis, Okubo et al[26] demonstrated that heme-activated platelets released
from necrotic muscle promoted release of macrophage extracellular traps. The role of
innate immune cells in inflammation and apoptosis is further supported by Kim et
al[27], noting macrophage depletion is protective against AKI. In humans, Pereira et al[28]
supported the concept of systemic inflammation in a case report of a soldier who
presented with exertional rhabdomyolysis. Investigations showed elevated levels of
proinflammatory cytokines (interleukin-1 and interleukin-6) and microvascular
dysfunction which persisted for one week.
There is paucity of basic science research in the liver context, particularly for a
direct role of myoglobin in inciting liver injury. There are limited studies implicating
oxidative stress in the liver related to rhabdomyolysis. Pal et al[20] examined the effects
of intense exercise in post-pubertal boys and girls, and demonstrated elevated serum
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CK and aminotransferases at 24 h and 48 h post-exertion. As evidence of oxidative
stress, they showed that serum catalase activity and thiobarbituric acid-reactive
substances (a marker of lipid peroxidation) were increased above baseline[20].
Georgakouli et al[29] also reported similar findings of increased aminotransferases,
catalase and total antioxidant capacity in heavy alcohol drinkers after moderate
intensity exercise.
CLINICAL QUESTIONS AND NOVEL APPROACHES
In the setting of rhabdomyolysis, what is an expected level of ALT rise given the
degree of muscle injury? In other words, is there a threshold for concern to justify
further tests for liver disease? Alternatively, can we use other markers to help clinical
decision making?
Adjusted analysis of traditional biomarkers
One simple idea is to adjust the aminotransferase level for other markers concurrently
released by injured muscles but not liver. The most relevant in rhabdomyolysis is the
CK/ALT ratio. Wang et al[30] examined the CK/ALT and CK/AST ratios in an
experimental model of dystrophinopathy associated with acute liver injury, and in
humans with dystrophinopathy. The authors reported that the CK/ALT ratio can
differentiate between normal liver, acute liver injury and dystrophinopathy with or
without liver injury, in their mouse model. In their patients, the CK/ALT ratio
showed promise as it was less affected by age and other factors associated with
muscle injury. Radke et al[31] demonstrated a significantly higher CK/ALT and
CK/AST ratios in patients with rhabdomyolysis compared to patients who overdose
on acetaminophen. The median CK/ALT ratio was 37.1 with rhabdomyolysis
compared to 5.8 with acetaminophen overdose. At a cut-off CK/ALT ratio of 15, the
sensitivity was 67% and specificity was 77%[31]. To differentiate liver from muscle
injury, a high specificity is desirable, thus the CK/ALT ratio is far from ideal but an
improvement on ALT alone. Given the non-linear correlation between CK and ALT,
the utility of the ratio of the log-transformed CK to log-transformed ALT should be
further studied[6].
Novel biomarkers
Looking beyond CK and aminotransferases, plasma microRNAs (miRNAs) show
promise. MicroRNAs are small, endogenous non-coding RNA molecules of around 22
nucleotides, which serves as gene regulators. Some microRNAs are cell and tissue-
specific, and generally remain stable in plasma. They can be measured with sensitive
molecular methods. In animal experiments, Laterza et al[32] examined miR-122 and
miR-133a for liver and muscle injury, respectively. miR-122 was elevated in liver but
not muscle injury, and miR-133a was elevated in muscle but not liver injury. Bailey et
al[33] conducted an extensive evaluation of miRNAs with the goal of utilising them in
clinical trials to distinguish liver from muscle injury. Among the promising
candidates were miR-1, miR-133a, miR-133b and miR-206 for muscle, and miR-122
and miR-192 for liver. In animal experiments, these biomarkers showed superior
specificity to CK and aminotransferases for muscle and liver injury respectively[33].
Goldstein[34] reported on work of the Predictive Safety Testing Consortium, which
included a muscle injury biomarker panel. The biomarkers were CK (mass assay),
fatty acid-binding protein 3, skeletal troponin I and myosin light chain 3.
Experimentally, the accuracy of these biomarkers was assessed in tetramethyl-p-
phenylenediamine induced skeletal muscle injury and acetaminophen-induced liver
injury. AST levels could not be used to distinguish liver from muscle injury but the
novel biomarkers showed higher specificity and correctly determined which tissue
was injured histologically[34].
Quantitative analysis and potential confounders
Some studies suggest that the relationship between serum CK and aminotransferases
is approximately linear. In muscular dystrophy, Wang et al[30] showed a positive linear
correlation between CK and ALT (r = 0.75), and between CK and AST (r = 0.79). The
levels of CK and aminotransferases were dependent on age but this variability was
diminished with the CK/ALT ratio. However, data from Weibrecht et al[35] suggested
that neither ALT nor peak CK is normally distributed in rhabdomyolysis. Lim et al[6]
confirmed this, and showed by linear and polynomial regression that the best
functional form of this association is a linear relationship between the log-transformed
CK and log-transformed ALT. The log-transformed CK, AKI stage, chronic liver
disease and age together accounted for 46% of the observed variance in ALT. It is also
possible to predict the ALT based on a regression model with these factors. In the
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worst case scenario, it was not common (< 5% chance) for the predicted serum ALT to
exceed 500 U/L (for peak CK up to 160000 U/L), on average[6]. Even extrapolating to a
peak CK of 400000 U/L, it was unlikely (< 1% chance) for it to exceed 800 U/L.
In such quantitative studies, consideration of confounding is important. One
important factor is kidney function. Aminotransferases are much higher in patients
with rhabdomyolysis and AKI compared to those without AKI[6,36]. On the other hand,
there is an ordinal relationship between chronic kidney disease (CKD) and baseline
aminotransferase levels. Compared to healthy individuals, patients with pre-dialysis
CKD have lower aminotransferase levels, while patients on dialysis have the lowest
levels[37,38]. Serum aminotransferases are also affected by age. In patients with
rhabdomyolysis, Lau-Hing Yim et al[39] noted that peak CK showed a negative linear
correlation with age (r = -0.42). However, AST tends to be more stable and as a result,
the AST/ALT ratio increases with age[40,41]. Elinav et al[42] proposed an inverted U-
shaped relationship between age and ALT. In their analysis, they included patients
with a wide age range and showed that ALT peaked at 40-55 years. In multiple
regression, age-squared and sex showed a statistically significant association with
ALT activity[42]. Finally, there may be a sex difference as well, with some studies
indicating that females have a lower baseline aminotransferase and CK levels than
men[42,43], while the post-exercise rise in CK was lower in females[19]. In addition to age
and sex, paediatric studies have also showed that body mass index and pubertal stage
influenced ALT levels[44].
CONCLUSION
In patients with an isolated rise in aminotransferases, rhabdomyolysis should be
considered in the differential diagnosis but current diagnostic tools do not have
adequate specificity to differentiate liver injury from isolated muscle injury. Further
research is required to meet this clinical need, and novel approaches and biomarkers
may prove useful. The predicted ALT from regression modelling and the biochemical
pattern and trajectory may be useful adjuncts to guide decision making whether more
extensive or invasive tests for liver disease is warranted in patients with
rhabdomyolysis.
ACKNOWLEDGEMENTS
I would like to thank Marcus Robertson, my gastroenterology colleague, for his
insightful comments on this topic.
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