How to investigate mildly elevated liver transaminase levels

Mild elevations in the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST) are commonly found in asymptomatic patients.

The most common cause is nonalcoholic fatty liver disease (sometimes called nonalcoholic steatohepatitis or NASH), which can affect up to 30% of the U.S. population.

Other common liver causes include:

- alcoholic liver disease
- medication-associated liver injury
- viral hepatitis (hepatitis B and C)
- hemochromatosis



Pale stool and dark urine (click to enlarge the images). This is an example of "obstructive" jaundice with the classic constellation of tea-colored urine and clay-colored stool.

Less common liver causes include:

- alpha-1-antitrypsin deficiency (AAT)
- autoimmune hepatitis
- Wilson disease

Extrahepatic conditions can also cause elevated liver transaminase levels:

- thyroid disorders
- celiac disease
- hemolysis
- muscle disorders

Initial testing should include:

- fasting lipid profile (FLP)
- measurement of glucose
- serum iron and ferritin; total iron-binding capacity (TIBC)
- hepatitis B surface antigen and hepatitis C virus antibody

If above test results are normal, a trial of lifestyle modification is appropriate.

Additional testing may include:

- ultrasonography (USG) of liver
- alpha-1-antitrypsin (AAT) and ceruloplasmin
- serum protein electrophoresis (SPEP)
- antinuclear antibody (ANA), smooth muscle antibody (ASMA), and liver/kidney microsomal antibody type

GI evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for more than 6 months.

References:

Causes and evaluation of mildly elevated liver transaminase levels. Oh RC, Hustead TR. Am Fam Physician. 2011 Nov 1;84(9):1003-8.

Alcohol consumption and raised body mass index (BMI) act together to increase risk of liver disease

Drinkers of 15 or more units per week in any BMI category and obese drinkers had raised relative rates for all definitions of liver disease, compared with underweight/normal weight non-drinkers.

The relative excess risk due to interaction between BMI and alcohol consumption was 5.58.

Raised BMI and alcohol consumption are both related to liver disease, with evidence of a supra-additive interaction between the two.

The occurrence of both factors in the same populations should inform health promotion and public health policies.

References:

Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. BMJ 2010;340:c1240.
Alcohol literally kills: Gary Moore had 380mg/dL in his blood, Winehouse 416mg/dL when she died surrounded by 3 empty vodka bottles. Telegraph UK, 2012. 

Image source: Wikipedia, public domain.

Statins Use in Presence of Elevated Liver Enzymes: What to Do?

The beneficial role of statins in primary and secondary prevention of coronary heart disease has resulted in their frequent use in clinical practice.

However, safety concerns, especially regarding hepatotoxicity, have driven multiple trials, which have demonstrated the low incidence of statin-related hepatic adverse effects. The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis, in which liver enzyme levels are elevated in the absence of proven hepatotoxicity.

"Ttransaminitis" is usually asymptomatic, reversible, and dose-related.


Lovastatin, a compound isolated from Aspergillus terreus, was the first statin to be marketed for lowering cholesterol. Image source: Wikipedia, public domain.

The increasing incidence of chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis C, has created a new challenge when initiating statin treatment. These diseases result in abnormally high liver biochemistry values, discouraging statin use.

A PubMed/MEDLINE search of the literature (1994-2008) was performed for this Mayo Clinic Proceedings review. The review supports the use of statin treatment in patients with high cardiovascular risk whose elevated aminotransferase levels have no clinical relevance or are attributable to known stable chronic liver conditions.

References:
Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Rossana M. Calderon, MD, Luigi X. Cubeddu, MD, Ronald B. Goldberg, MD and Eugene R. Schiff, MD. Mayo Clinic Proceedings April 2010 vol. 85 no. 4 349-356.

Statins slightly increase risk of cataracts, liver dysfunction, kidney failure and muscle weakness

Statins do NOT prevent a long list of diseases

Statins were not significantly associated with risk of Parkinson’s disease, rheumatoid arthritis, venous thromboembolism, dementia, osteoporotic fracture, gastric cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer.

Statins may decrease risk of esophageal cancer

Statin use was associated with decreased risks of oesophageal cancer.

Statins slightly increase the risk of liver dysfunction, kidney failure, muscle weakness and cataracts

Statin use was associated with increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract.

Is the risk the same with all statins?

Adverse effects were similar across statin types for each outcome except liver dysfunction where risks were highest for fluvastatin.

A dose-response effect was apparent for acute renal failure and liver dysfunction. All increased risks persisted during treatment and were highest in the first year.

How long does the risk last?

After stopping treatment the risk of cataract returned to normal within a year in men and women. Risk of acute renal failure returned to normal within 1-3 years in men and women, and liver dysfunction within 1-3 years in women and from three years in men.

What was the NNT and NNH?

Based on the 20% threshold for cardiovascular risk, for women the NNT with any statin to prevent one case of cardiovascular disease over five years was 37 and for oesophageal cancer was 1266 and for men the respective values were 33 and 1082.

In women the NNH for an additional case of acute renal failure over five years was 434, of moderate or severe myopathy was 259, of moderate or severe liver dysfunction was 136, and of cataract was 33. Overall, the NNHs and NNTs for men were similar to those for women, except for myopathy where the NNH was 91.

Conclusion

Claims of unintended benefits of statins, except for oesophageal cancer, remain unsubstantiated, although potential adverse effects at population level were confirmed and quantified.

Interestingly, the BMJ abstract did not mention increased diabetes risk that was reported in a previous study published in The Lancet.

References:

Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010; 340:c2197 doi: 10.1136/bmj.c2197 (Published 20 May 2010).

Balancing the intended and unintended effects of statins. BMJ 2010; 340:c2240 doi: 10.1136/bmj.c2240 (Published 20 May 2010).

People on statins are 9% more likely to develop diabetes according to a meta-analysis
Cholesterol drug side effects need watching: study. Reuters.

Image source: Simvastatin. Wikipedia, public domain.