What Should I Do With This Abnormal ALT?

JUNE 09, 2015
Francisco A. Durazo, MD, FACP
You see a 48-year-old white man for his annual examination. He is in good health with no major medical problems and an unremarkable medical history. He states he regularly drinks one or two beers a day on the weekend but not usually on weekdays. He denies blood transfusions, tattoos or intravenous drugs. His father had diabetes. The patient is overweight with a body mass index (BMI) of 32. A screening chemistry panel is normal except for an aspartate aminotransferase (AST, formerly SGOT) level of 85 U/L (normal 15-50 U/L) and an alanine aminotransferase (ALT, formerly SGPT) level of 98 U/L (normal 5-50 U/L). He says you are the first doctor he has seen in more than 10 years and does not recall the last time he had a blood test.

What is your differential diagnosis, and what laboratory tests would you order?
Mild abnormal elevation of the aminotransferases is common in everyday practice. Most of the patients are asymptomatic and the liver test abnormalities are discovered incidentally during a routine check up or, sometimes when applying for a life insurance policy. It is important to see if these abnormalities are chronic or just of short duration and self limited. Liver test abnormalities of short duration and self limited are usually caused by medications, supplements or another underlying disease. The differential diagnosis in this patient includes nonalcoholic fatty liver disease (NAFLD)) since this is, by far, the most common cause of abnormal liver tests in the United States. Other possibilities include viral hepatitis (HBV, HCV and HEV), autoimmune hepatitis, iron storage disease, Wilson disease, alpha 1 antitrypsin deficiency and celiac sprue. Alcohol abuse is a consideration however, less likely because of the AST/ALT ratio. In alcoholic liver disease the AST is higher than the ALT.
The laboratory tests for the evaluation of this patient include: HBsAg, HB core Ab, HCV Ab, ANA, SMA, ferritin, transferring saturation, ceruloplasmin, alpha 1 antitrypsin phenotype and tissue transglutaminase.
Hepatitis serologies are negative.  Results of antinuclear and smooth muscle antibody testing are negative. The serum iron value is 100 g/dL, the serum iron-binding capacity is 410 g/dL and serum ferritin is 70 g/L. His serum ceruloplasmin is normal as is his alpha-1-antitrypsin levels and tissue transglutaminase. The patient denies exposure to hepatotoxins.  

After 6 months, the aminotransferase values are unchanged even though the patient lost 5 pounds. What now?
Improvement of the aminotransferases after weight loss is suggestive of NAFLD as the cause of aminotransferase elevations. In the case of this patient, a 5 lb weight loss is insignificant. Obese patients with aminotransferase elevations due to fatty liver need to lose at least 10% of their weight to see improvement in aminotransferase levels and metabolic syndrome. At this point, an  imaging study to rule out fatty liver would be the next step in the evaluation of this patient.
What test would you order?
Preferably an abdominal ultrasound. Abdominal ultrasound and CT scan can detect fatty infiltration of the liver >95% of the cases, when fatty infiltration exceeds 30%. Abdominal ultrasound sometimes can be difficult in very obese patients. Imaging studies are the preferred test for the diagnosis of NAFLD; however, they are not able to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Only with a liver biopsy we can distinguish simple steatosis from NASH.

A right upper quadrant ultrasound examination that shows fatty liver with no evidence of biliary disease.
How is the diagnosis of NAFLD made?

The diagnosis is made by demonstrating the presence of hepatic steatosis, either by imaging or histology, and establishing the nonalcoholic nature of the disease process. Demonstrating the presence of hepatic steatosis is not a problem. It can be done with an abdominal ultrasound.  To establish the nonalcoholic nature of the disease can be cumbersome. Because of the lack of objective parameters, we must rely on patient information regarding alcohol intake. Liver histology is not helpful. The cut off regarding alcohol intake for males is <40 g/day and for females <20 g/day. Obviously, secondary hepatic steatosis should be excluded.
What are causes of secondary hepatic steatosis?
Secondary causes of hepatic steatosis can be subdivided into causes of macrovesciular and microvesicular steatosis. Causes of macrovesicular steatosis include excessive alcohol consumption, hepatitis C (particularly genotype 3), Wilson’s disease, lipodystrophy, rapid weight loss and starvation, parenteral nutrition, abetalipoproteinemia, and certain drugs (e.g. amiodarone, methotrexate, corticosteroids, tamoxifen). Causes of microvesicular steatosis are less common and include drug-induced (e.g. valproate, anti-retroviral medicines), Reye’s syndrome, specific pregnancy syndromes (e.g. acute fatty liver of pregnancy, HELLP syndrome), polycystic ovary syndrome, as well as certain inborn errors of metabolism (e.g. Lecithin cholesterol acyltransferase deficiency, Wolman disease, cholesterol ester storage disease).* Most of these diseases can be diagnosed by a good history and physical, and laboratory tests. Some may require a liver biopsy.

How common is NAFLD?
The prevalence of NAFLD has increased substantially over the last decades. It has become the most common liver disorder in the world. A recent large, biopsy-based, prospective cross sectional study found a prevalence of NAFLD of 46%; NASH was confirmed in 12.2% of total cohort, 29.9% of ultrasound positive patients. Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older, hypertensive, and diabetic. They had a higher BMI, ate fast food more often, and exercised less than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs. 9.8%). In 2008, a genome-wide association (GWAS) study revealed the presence of the allele patatin-like phospholipase 3 (PNPLA 3) to be associated with increased hepatic fat content, hepatic inflammation and risk for hepatocellular carcinoma. The allele was most common in Hispanics.

What is the natural history of NAFLD?
The evolution of hepatic histologic changes in patients with NAFLD has been investigated by several studies, but these generally included smaller number of patients and had a relatively modest duration of follow up. Nonetheless, patients with NAFLD have increased overall mortality compared to matched control populations. The most common cause of death in patients with NAFLD is cardiovascular disease.  In terms of potential for progression, NAFLD patients fall into 2 broad categories: NASH and non-NASH. The non-NASH subtype includes all patients with simple steatosis as well as patients with steatosis and nonspecific changes. Although NASH can follow a potentially progressive course for liver disease, the non-NASH subtype does not progress or progress very slowly. Hepatic injury induced by NASH is similar to that caused by alcohol-induced liver disease; however, NASH seems to progress more slowly. 32-53% of the patients with NASH are going to have histological progression with increased inflammation and fibrosis, and higher liver related mortality. The development of hepatocellular carcinoma is a concern and can occur in non-cirrhotic livers (steatohepatitic hepatocellular carcinoma). Insulin resistance, diabetes mellitus and other components of the metabolic syndrome are risk factors for developing advanced liver disease.
*Hepatology 2012;55(6):2005-23,

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