Investigating mildly abnormal serum aminotransferase values
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4039 (Published 30 July 2010) Cite this as: BMJ 2010;341:c4039
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Liver disease is the most prevalent cause of raised serum
aminotransferases and is addressed in the recent article by Cobbold and
colleagues (1). However, the article does not mention screening for muscle
disease, particularly in those patients with a normal bilirubin, GGT and
liver ultrasound.
Important extra-hepatic sites of aminotransferase synthesis include
the brain, erythrocytes, kidney, skeletal and cardiac muscle (2). Their
relative contribution to normal serum aminotransferase levels is still
poorly understood. Amongst the aminotransferases, ALT is regarded as being
more specific than AST for hepatocellular injury. However several reports
indicate that various extra hepatic diseases, including those involving
skeletal muscle will increase both serum AST and ALT levels (3).
Myocyte injury and necrosis following strenuous exercise, toxins,
drugs and rhabdomyolysis will lead to a transient and ‘short-lived’ rise
in both AST and ALT (4). Chronic muscle injury secondary to inflammatory
muscle diseases, muscular dystrophies, mitochondrial, endocrine and
metabolic myopathies will result in a sustained increase in both
aminotransferases, which may vary widely in magnitude (3). Serum
creatinine kinase (CK) is a sensitive marker of muscle injury and this
should be measured when muscle disease is suspected.
Cobbold and colleagues describe the case of a 42 year old man with a
mild increase in AST and ALT (1). In this age group the inflammatory
muscle diseases such as polymyositis and dermatomyositis need to be
excluded. These diseases may have a bad prognosis and require early
recognition and prompt treatment. In early disease patients may present
with constitutional symptoms in the absence of significant muscle
weakness, and a routine blood panel may reveal elevated transaminases.
Proximal muscle weakness, dysphagia and shortness of breath will become
clinically evident as disease progresses and heralds a bad prognosis.
Further investigation with serial CK measurements, electromyography,
muscle MRI, muscle biopsy, autoantibody profile and a screen for
malignancy is then warranted (5).
It follows that any patient with an unexplained rise in AST and/or
ALT with normal bilirubin, GGT and liver ultrasound scan should be
carefully assessed for muscle disease. This should include a clinical
assessment for muscle weakness, dysphagia, shortness of breath and
measurement of CK. A raised CK in this context will indicate muscle
disease and should prompt a referral to a rheumatologist or neurologist
for further investigation and treatment.
References
(1) Cobbold JF, Anstee QM, Thomas HC. Investigating mildly abnormal
serum aminotransferase values. BMJ 2010; 341:c4039.
(2) Wroblewski F. The clinical significance of alterations in
transaminase activities of serum and other body fluids. Adv Clin Chem
1958; Vol. 1(2):313-351.
(3) Green RM, Flamm S. AGA technical review on the evaluation of
liver chemistry tests. Gastroenterology 2002; 123(4):1367-1384.
(4) Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine
aminotransferase in skeletal muscle diseases. Hepatology 2005; 41(2):380-
382.
(5) Limaye VS, Blumbergs P, Roberts-Thomson PJ. Idiopathic
inflammatory myopathies. Intern Med J 2009; 39(3):179-190.
Competing interests:
None declared
Competing interests: No competing interests
I think that hepatitis B and C screen should be done especialy if GGT
IS normal and no macrocytosis particularly for patients from third world
countries.
Competing interests:
None declared
Competing interests: No competing interests
Cobbold and colleagues state that gamma-glutamyltransferase (GGT)
should be measured in all patients with raised serum alanine
aminotransferase (ALT) because if elevated it would indicate alcohol
related liver disease [1]. GGT, because of its ubiquitous distribution
within the liver, is elevated in all types of liver disease [2]. In the
absence of significant liver disease, the myth that a raised GGT is
sensitive and specific for alcohol excess persists. In these
circumstances, for example, GGT is elevated in only 52% of alcoholic
patients [3] but also raised in 50% of patients with non-alcoholic fatty
liver disease (NAFLD) [4]. Guidelines recommend that measurement of GGT
be limited to identifying the likely origin of an isolated raised
Alkaline Phosphatase (ALP), because if elevated it indicates a hepatic
rather bony origin for the raised ALP [2, 5,6]. In this case study, GGT
was elevated but the final diagnosis was NAFLD [1]. We, therefore,
suggest that measurement of GGT in the investigation of raised serum
transaminases is not only unnecessary but potentially misleading as
illustrated in this case study.
References:
1.Cobbold JFL, Anstee QM, Thomas HC, Investigating mildly abnormal
serum aminotransferase values. BMJ 2010;341:c4039
2. Green RM, Flamm S. AGA technical review on the evaluation of liver
chemistry tests. Gastroenterology. 2002;123:1367-84.
3. Moussavian SN, Becker RC, Piepmeyer JL Mezey E, Bozian RC Serum
gamma-glutamyl transpeptidase and chronic alcoholism. Influence of alcohol
ingestion and liver disease. Dig Dis Sci. 1985; 30: 211-4
4. McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin
Gastroenterol. 2002; 34:255-62
5.Smellie WSA, Forth J, Ryder S, Galloway MJ, Wood AC, Watson ID.
Best practice in primary care pathology: review 5. J Clin Pathol. 2006;
59: 1229–37.
6. AGA. American Gastroenterological Association medical position
statement: evaluation of liver chemistry tests. Gastroenterology.
2002;123:1364-6.
Competing interests:
None declared
Competing interests: No competing interests
Editor—Cobbald et al provided an excellent review of the
investigation of the patient with mildly abnormal serum aminotransferase
values.1 However, one medical condition that was not mentioned was coeliac
disease.
Population screening in the United Kingdom has suggested that coeliac
disease has a prevalence of 1%, and the majority of these patients are
unrecognised.2 The association of coeliac disease with either an isolated
hypertransaminasaemia or coexistent autoimmune liver disease is well
described.3 Persistently abnormal liver function tests may be the only
presenting feature of coeliac disease. Several studies have reported that
up to 9% of patients presenting with cryptogenic hypertransaminasaemia
have underlying undetected coeliac disease.3 Furthermore the liver
function tests normalise on a gluten-free diet.
The difficulty of early clinical detection, associated complications, and
availability of effective treatment with a gluten free-diet has led to a
debate about mass population screening for coeliac disease.4 The recent
NICE guidelines support an active case-finding approach and recommends
that patients with persistently raised liver enzymes of unknown cause, and
those with autoimmune liver disease should be considered for serological
testing.5
The relationship between coeliac disease and liver disease continues to be
a neglected association in clinical practice. Testing is sensitive,
specific, cheap and readily available. We would suggest that anti –tissue
transglutaminase (tTG) and anti-endomysial antibody (EMA) be included in
the screening tests for liver disease. These antibodies are not considered
part of the existing antibody profile and as such will not be tested for
without a specific request. We would urge clinicians to consider these
additional tests as part of their rational testing strategy for
investigating mildly abnormal serum aminotransferase values.
1. Cobbold JF, Anstee QM, Thomas HC. Investigating mildly abnormal
serum aminotransferase values. BMJ. 2010;341:c4039.
2. Evans KE, Leeds JS, Sanders DS. Be vigilant for patients with
coeliac disease. Practitioner. 2009;253:19-22.
3. Volta U. Pathogenesis and clinical significance of liver injury in
celiac disease. Clin Rev Allergy Immunol. 2009;36:62-70.
4. Evans KE, McAllister R, Sanders DS. Should we screen for coeliac
disease? No. BMJ. 2009;339:b3674.
5. Richey R, Howdle P, Shaw E, Stokes T; Guideline Development Group.
Recognition and assessment of coeliac disease in children and adults:
summary of NICE guidance. BMJ. 2009;338:b1684.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
Cobbold et al have published a very useful article on this topic but
I'm quite surprised the authors haven't mentioned coeliac disease as a
possibility in a patient with a persistent transaminase enzyme increase as
this relationship is well described.
We've uncovered a considerable number of patients with latent coeliac
disease by requesting tissue transglutaminase antibodies if we find
persistently raised transaminase enzymes that we could not otherwise
explain.
(Gonzalez-Abraldes J, Sanchez-Fueyo A, Bessa X, et al. Persistent
hypertransaminasemia as the presenting feature of celiac disease. Am J
Gastroenterol, 1999;94:1095-1097.
Bardella MT, Vecchi M, Conte D, et al. Chronic unexplained
hypertransaminasemia may be caused by occult celiac disease.
Hepatology,1999;29:654-657.)
Dr David Sinclair
Head of Blood Sciences
Queen Alexandra Hospital,
Portsmouth
PO6 3LY
david.sinclair@porthosp.nhs.uk
Competing interests:
None declared
Competing interests: No competing interests
The authors deserve a bravery medal for addressing the controversies surrounding the current epidemic of non alcoholic fatty liver disease (steatosis) and its advanced stage non alcoholic steatohepatitis (NASH) that includes inflammation, hepatocyte necrosis and fibrosis.
The authors recommend waiting 3 months to follow-up a mildly elevated serum alanine aminotransferase in an asymptomatic patient without jaundice. Should we recommend strict abstinence from ethanol during this period? What was the follow-up interval in the reported case? The authors recommend adding serum aspartate aminotransferase and serum gamma glutamyl aminotransferase assays to the follow-up. Just considering the normal/abnormal dicotomy, these three liver enzyme assays will result in 8 different combinations of results. What should we do when only one enzyme is elevated? Only two? What should we do if the alanine aminotransferase increases? Or, decreases as in the reported case? Should we wait another 3 months for further improvement? What is the prevalence of steatosis alone in those cases for whom all three enzymes are normal on follow-up? Likewise, what is the prevalence of NASH when all three enzymes are normal?
If my ultrasound scan had a sensitivity of 94%, then I could rule out steatosis with this relatively low cost test without risk to the patient, but if my sensitivity is only 60%, I might as well flip a coin. How can I learn what is the sensitivity of my liver ultrasound scan? In Texas, we have an epidemic of obesity. How much does obesity further decrease the sensitivity of an ultrasound scan? If the ultrasound probe is aimed caudad through the lower sternum, does that mitigate the effect of thick subcutaneous fat?
Should HOMA-IR or fasting serum insulin be a follow-up test? If so, where does it fit in your flow-chart?
The reported case was "treated with drugs combined with dietary and lifestyle modification." Which drugs at what doses were prescribed? Vitamin E? Pioglitazone? Other? The PRIVENS trial suggests that vitamin E or pioglitazone improve biopsy confirmed NASH. Is there any evidence, even a case series, that combining vitamin E with pioglitazone is better than either of these alone?
Did the reported case have a follow-up biopsy? If so how long did you wait to give the treatment a chance to show improvement on biopsy? If not, can we assume that improvement in serum liver enzymes implies improvement on biopsy?
What is the cost of this guideline when applied to a population with an epidemic of insulin resistance or metabolic syndrome? Do we really need to rule out haemachromatosis, alpha-1-antitrypsin deficiency and Wilson's disease in patients without clinical evidence? Can we substitute a serum haemaglobin A1c for an oral glucose tolerance test and save the patient 3 hours away from their job?
When magnetic resonance spectroscopy becomes clinically available, what will it cost? What will be the indications for a MRS liver scan? Will it change indications for a liver biopsy? For treatment? For treatment follow-up?
Competing interests:
None declared
Competing interests: No competing interests
Although not mentioned by the authors(1), attention needs to be
drawn, as in a recent review, to the association of Addison's disease and
elevation of alanine aminotransferase(ALT) and aspartate
aminotransferase(AST), respectively(2).
A review of 17 published cases of
this association documented that, in eleven of those instances, fatigue
was also a feature, and that in the remaining six without this symptom,
pointers to endocrine disease were found in four, namely, Addisonian
crisis in two, and hyperpigmentation and dysmenorrhoea, respectively, in
two others. Only two of the seventeen patients were asymptomatic at the
time of presentation with abnormal transaminases. Although, at the time of
writing (in 2009), the underlying pathophysiology of the liver dysfunction
remained speculative(2), the underlying message for clinicians is that
symptoms and signs of Addison's disease should also be actively sought in
patients who present with unexplained elevation of ALT and AST.. Secondary
hypoadrenalism, too, may be associated with raised ALT and AST, although,
in this context, hepatic dysfunction may have been attributable to hepatic
congestion consequent of hypoadrenalism-related pericardial effusion with
tamponade(3).
A recent review also drew attention to the fact that
elevation in ALT and AST can occur in as many as 27% and 37%,
respectively, of patients with hyperthyroidism, and that jaundice and
severe cholestasis can occur in some instances(4). In the context of
hyperthyroidism hepatic dysfunction is thouht to be attributable to
mitochondrial dysfunction(4). At the other extreme is the association of
hypothyroidism and hepatic dysfunction, exemplified by the fact that "[a]
prevalence of hypothyroidism in patients with NASH(nonalcoholic
steatohepatitis) [is] double that seen in controls(odds ratio 2.3, 95% CI
1.2-4.2)". Citing this statistic, the authors suggested that
hypothyroidism, via hyperlipidaemia and obesity, might trigger the
NAFLD(non-alcoholic fatty liver disease)-mediated chain of event that lead
to NASH(4)
References
(1) Cobbold JFL., Anstee QM., Thomas HC
Investigating mildly abnormal serum aminotransferase values
BMJ 2010;341:297-9
(2) Kalambokis GK., Milionis HJ
Addison's disease and hypertransaminasemia
Expert Rev Endocrinol Metab 2009;4:251-261
(3) Desai NR., Cheng S., Nohria A., Halperin F., Guigliano RP
When past is prologue
N Engl J Med 2009;360:1016-22
(4) Loria P., Carulli L., Bertolotti M., Lonardo A
Endocrine and liver interaction: the role of endocrine pathways in NAS
Nat Rev Gastroenetrol Hepatol 2009;6:236-47
Competing interests:
None declared
Competing interests: No competing interests
Editor;
We read the article by Cobbold et al. concerning investigation of
mildly abnormal serum aminotransferases with interest. (1) Whilst we agree
with the authors that hepatitis B and C, genetic haemochromatosis, alpha-1
anti-trypsin deficiency, Wilson’s disease, and autoimmune liver disease
are all important, and potentially treatable, causes of elevated
transaminases, we were very surprised that the authors did not advocate
screening for coeliac disease routinely as part of their workup.
Coeliac disease is a common disorder in the general population, with
a prevalence of 1% in the West. (2) It presents classically with diarrhoea
and evidence of malabsorption, such as iron deficiency anaemia or
hypocalcaemia. However, the disease may also present with Protean
manifestations, such as non-specific abdominal pain, (3) symptoms
suggestive of irritable bowel syndrome, (4) and also with abnormal serum
aminotransferases.
Transaminitis may be present in between 20% and 40% of individuals
with coeliac disease at presentation, (5, 6, 7) and these abnormalities
often return to normal with institution of a gluten-free diet. (6, 7) In
addition, studies that have screened individuals with otherwise
unexplained hypertransaminasaemia for coeliac disease using serological
testing, such as tissue transglutaminase or anti-endomysial antibodies,
consistently demonstrate prevalences for seropositivity between 9% and
12%. (8, 9, 10) Finally, there is some evidence to suggest that coeliac
disease is more common in individuals with autoimmune hepatitis than in
controls without. (11)
We believe, therefore, that the diagnosis of coeliac disease should
be excluded routinely, with serological testing followed by distal
duodenal biopsy in those who test positive, in individuals who present
with unexplained abnormalities of serum aminotransferases.
Dr. Anita Sainsbury
Dr. Alexander C. Ford
Leeds Gastroenterology Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX
References
1. Cobbold JFL, Anstee QM, Thomas HC. Investigating mildly abnormal
serum aminotransferase values. Br Med J 2010;341:c4039.
2. Sanders DS, Patel D, Stephenson TJ, Ward AM, McCloskey EV,
Hadjivassiliou M, Lobo AJ. A primary care cross-sectional study of
undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;15:407
-413.
3. Ford AC, Chey WD, Talley NJ, Malhotra A, Spiegel BM, Moayyedi P.
Yield of diagnostic tests for celiac disease in individuals with symptoms
suggestive of irritable bowel syndrome: systematic review and meta-
analysis. Arch Intern Med 2009;169:651-658.
4. Sanders DS, Hopper AD, Azmy IA, Rahman N, Hurlstone DP, Leeds JS,
George RR, Bhala N. Association of adult celiac disease with surgical
abdominal pain: a case-control study in patients referred to secondary
care. Ann Surg 2005;242:201-207.
5. Bode S, Gudmand-Hoyer E. Symptoms and haematologic features in
consecutive adult coeliac patients. Scand J Gastroenterol 1996;31:54-60.
6. Novacek G, Miehsler W, Wrba F, Ferenci P, Penner E, Vogelsang H.
Prevalence and clinical importance of hypertransaminasaemia in coeliac
disease. Eur J Gastroenterol Hepatol 1999;11:283-288.
7. Bardella MT, Fraquelli M, Quatrini M, Molteni N, Bianchi P, Conte
D. Prevalence of hypertransaminasemia in adult celiac patients and effect
of gluten-free diet. Hepatology 1995;22:833-836.
8. Lo Iacono O, Petta S, Venezia G, Di Marco V, Tarantino G, Barbaria
F, Mineo C, De Lisi S, Almasio PL, Craxi A. Anti-tissue transglutaminase
antibodies in patients with abnormal liver tests: is it always celiac
disease? Am J Gastroenterol 2005;100:2472-2477.
9. Volta U, Granito A, De Franceschi L, Petrolini N, Bianchi FB. Anti
tissue transglutaminase antibodies as predictors of silent coeliac disease
in patients with hypertransaminasaemia of unknown origin. Dig Liver Dis
2001;33:420-425.
10. Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M, Bianchi FB.
Coeliac disease hidden by cryptogenic hypertransaminasaemia. Lancet
1998;352:26-29.
11. Villalta D, Girolami D, Bidoli E, Bizzaro N, Tampoia M, Liguori
M, Pradella M, Tonutti E, Tozzoli R. High prevalence of celiac disease in
autoimmune hepatitis detected by anti-tissue tranglutaminase
autoantibodies. J Clin Lab Anal 2005;19:6-10.
Competing interests:
None declared
Competing interests: No competing interests
We read with interest the Practise of Cobbold JF et al.(1) regarding
the investigation of slightly raised aminotransferase. The authors
consider numerous causes of hypertransaminasaemia, but they not consider
celiac disease (2).
Patients with persistent abnormal aminotransferase are undergone a
costly and time-consuming work-up for rarer diseases such as Wilson's
disease or a1-antitrypsin deficiency and even liver biopsy. Nevertheless,
the cause of these hypertransaminasaemia often remains undetermined.
Both Bardella and Volta (3,4) show that about 9% of patients with
cryptogenic hypertransaminasaemia are affected by symptom-free celiac
disease.
Celiac disease can be associated to a wide spectrum of liver injuries, in
particular to steatosis.
Bardella et al. (5) tested for celiac disease 59 consecutive patients with
hypertransaminasemia and non-alcoholic fatty liver disease; 2 out of 59
(3.4%) were positive for both anti-endomysium and anti-transglutaminase
antibodies and were resulted to have celiac disease on histological
findings.
Taking into account these observations, antibody screening for celiac
disease by means of antibodies to endomysium and transglutaminase must be
included in the clinical assessment of children and adults with abnormal
serum aminotransferase values.
References
1. Cobbold JF, Anstee QM, Thomas HC. Investigating mildly abnormal
serum aminotransferase values. BMJ 2010; 341:c4039. doi:
10.1136/bmj.c4039.
2. Richey R, Howdle P, Shaw E, Stokes T; Guideline Development Group.
Recognition and assessment of coeliac disease in children and adults:
summary of NICE guidance. BMJ. 2009;338:b1684. doi: 10.1136/bmj.b1684.
3. Bardella MT, Vecchi M, Conte D, et al. Chronic unexplained
hypertransaminasemia may be caused by occult celiac disease. Hepatology.
1999;29(3):654-7.
4. Volta U, De Franceschi L, Lari F, et al. Coeliac disease hidden by
cryptogenic hypertransaminasaemia. Lancet. 1998;352(9121):26-9.
5. Bardella MT, Valenti L, Pagliari C, et al. Searching for coeliac
disease in patients with non-alcoholic fatty liver disease. Dig Liver Dis.
2004;36(5):333-6.
Serena Pastore, MD, Federico Marchetti, MD
Department of Paediatrics, Institute of Child Health, IRCCS Burlo
Garofolo, Trieste
Via dell'Istria 65/1, 34100 Trieste, Italy
Corresponding author:
Serena Pastore, MD
phone +39 040 378454; fax +39 040 3785362
e-mail: pastore_serena@libero.it
Competing interests:
None declared
Competing interests: No competing interests
The importance of initial screening of mildly elevated abnormal serum aminotransferase levels without repeat testing
Cobbold and colleagues suggested that repeat testing of mildly raised
serum aminotransferases is warranted prior to screening for liver disease.
However, there are several important considerations related to Hepatitis
disease progression, demographics, and cost effectiveness that warrant
initial screening without repeat testing.
The American Gastroenterology Association (2002), Canadian Medical
Association (2005), and the Center for Disease Control (2006) all released
guidelines to screen patients with mild elevations of liver enzymes for
Hepatitis B(HBV) and Hepatitis C(HCV) without repeat testing.1 In
Hepatitis B and C, the liver function tests commonly fluctuate
intermittently from normal to abnormal and do not correlate well with
liver histology.2 At least 16% of patients with chronic Hepatitis C
infection and 13% of patients with nonalcoholic fatty liver disease have
varying degrees of histological damage despite showing persistently normal
aminotransferase levels.3,4 Thus, repeating an abnormal liver function
test and having a normal value on repeat testing does not ensure that the
initial value was erroneous, but rather proves that there is biochemical
variability. 1 Both HBV and HCV rapidly produce and viral loads can become
quite significant before any elevations of ALT/AST are observed. The
various manifestations of both diseases can also be seen with high viral
loads in the absence of transaminase elevations. Additionally, as viral
loads increase, there is an increased risk of viral mutations, increased
incidence of extraintestinal manifestations, increased incidence of
hepatocellular carcinoma, secondary treatment resistance, and an increased
risk for progression of disease.
Lastly, it is cost effective to initially screen for Hepatitis B and
C in areas with high prevalence of disease or high risk populations.5 We
therefore suggest that initial screening, without repeat testing be highly
considered in the aforementioned context.
References:
1. AGA Technical Review on the Evaluation of Liver Chemistry Tests,
GASTROENTEROLOGY 2002;123:1367-1384
2. Haber MM, West AB, Haber AD, Reuben A. Relationship of
aminotransferases to liver histological status in chronic hepatitis C. Am
J Gastroenterol 1995;90:1250 1257.
3. Gholson CF, Morgan K, Catinis G, Favrot D, Taylor B, Gonzalez E, et
al.Chronic hepatitis C with normal aminotransferase levels: a clinical
histological study. Am J Gastroenterol 1997;92(10):1788-92.
4 Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et
al.Clinical and histologic spectrum of nonalcoholic fatty liver disease
associated with normal ALT values. Hepatology 2003;37(6):1286-92.
5 Sroczynski G., Esteban E., et. all. Long-term effectiveness and cost-
effectiveness of screening for Hepatitis C virus infection.
Competing interests: No competing interests