Asymptomatic Transaminasemia: A Clinical Approach

Dr. Samir R. Shah, M.D., D.M., Consultant Gastroenterologist, Dr. Parijat Gupte, M.D, Clinical Assistant, Jaslok Hospital and Research Centre, Mumbai, India.

Case History:

25 years old male patient presented with elevated ALT/AST, which was detected during a febrile illness in 2000. He recovered and remained well but subsequent check up over the next two years showed persistently elevated ALT/AST. The patient was found to be other wise fit and exercised regularly. He had no past history of jaundice, blood transfusion or any surgery. He had no family history of diabetes, hypertension, Ischemic Heart Disease or liver disease.

The only positive history he gave was the fact that he consumed 120 ml of alcohol once a month since 1999 for 2 years. Later the consumption of alcohol had increased up to twice a month for a further 2 years.

Examination:

On examination he was found to have a just palpable non-tender liver with no stigmata of chronic liver disease.

Lab investigations:

AST and ALT were found to be elevated to 1.5 and 4 times the upper limit of normal respectively. Globulin levels were borderline elevated but albumin was normal, Alkaline phosphatase and GGTP were two times the upper limit of normal. Serum bilirubin and INR were normal.

Further investigation as noted in Table 1 did not find any evidence to implicate Chronic Hepatitis B or C, autoimmune liver disease or Wilson’s disease. Ultrasonography showed normal echotexture of the liver without any evidence of a fatty liver.

The patient has an identical twin brother who did not consume alcohol and had normal LFT. Both underwent investigations to look for insulin resistance. The only significant difference between the twin brothers being the patient having a comparatively higher waist hip ratio and a BMI above the upper limit of Indian normal.

Subsequent Treatment and outcome:

The patient was advised to stop intake of alcohol, which he reduced but did not stop completely. He continued to exercise regularly and followed the recommended diet to lose weight As the ALT and AST were found to remain persistently elevated over the next one year a liver biopsy was done in October 2003 which showed the liver architecture to be well maintained. Some of the cells were large with a vacuolated cytoplasm and an eccentrically placed nucleus. Some cells showed an eosinophilic granular cytoplasm. A focal mononuclear infiltrate was found in relation to the portal tract and between the hepatocytes. No necrosis, granuloma or evidence of cirrhosis was seen. Focal fatty changes with focal mononuclear infiltrate was noted.

The patient was treated with ursodeoxycholic acid since 2003. He stopped alcohol completely. However the serial LFT have not shown any significant decrease in ALT/AST, Alkaline phosphatase or GGTP.

Case Discussion:

Asymptomatic elevated transaminases are a common clinical problem. Detailed stepwise evaluation is necessary to find an etiology in these cases. It provides a window of opportunity in many cases where disease is identified in early stage and effective therapy can change the course of the disease.

The concerned patient was consuming approximately 240 ml of alcohol per month (80gms/month). Currently safe limit of alcohol consumption below which there is no significant rise in risk of alcohol related liver disease is 21 units (210gms) per week for men and 7 units (70gms) for females. Levels of alcohol consumption, taken as an exclusion criterion in various clinical trials for diagnosis of NonAlcoholicSteatoHepatitis (NASH), have increased over a period of time from 20gms/day to 20gms per week. There are subtle differences which can distinguish alcoholic from non alcoholic liver disease on a liver biopsies but at times in a given case even an expert liver pathologist may not be able to distinguish the two entities.

True “safe limit” for alcohol is difficult as susceptibility for Alcholic Liver Disease (ALD) would also depend on genetic factors, nutrition, diet, obesity, gender and associated virus infections. In the above mentioned patient alcohol intake lower than hazardous limits and ratio of ALT/AST more than 1 makes significant ALD unlikely.

Hepatitis B and Hepatitis C infections are common causes of chronic infections which remain silent for years. HBsAg and third generation Anti HCV assays are highly sensitive in an immunocompetent individual. Negative results make possibility of these infections less likely. An algorithmic approach has been suggested recently to highlight a small group of chronic viral hepatitis, which may be missed by serology and picked up only on virological testing.

Detailed drug history is essential in these individuals. Use of analgesics, alternative medicines and common drugs e.g. lipid lowering agents like statins may be overlooked as cause of elevated transaminases. Once these common causes are ruled out other possibility in a young individual are Autoimmune liver disease, or Wilson’s disease. Normal S. Ceruloplasmin, 24 hrs urinary copper, absent K-F rings and negative family history makes diagnosis of Wilson disease in this individual unlikely. Similarly possibility of autoimmune liver disease is less likely in absence of immunological markers and significant hypergamaglobulinemia, male gender and lack of evidence for other autoimmune disorders.

10-20% of the western population is estimated to have Non Alcoholic Fatty Liver Disease (NAFLD) and 2-3 % have NASH. NAFLD is common in individuals with the metabolic syndrome which is highlighted by obesity, hypertension, dyslipidemia and type II diabetes. 66% individuals with asymptomatic transaminases without evidence of any other etiology would be expected to have NAFLD on biopsy. Absence of serological and histological evidence of viral and autoimmune liver disease, lack of significant alcohol intake and increased BMI makes NAFLD a possible diagnosis in this case.

Although there is no evidence of steatosis on USG in the above patient, sensitivity of USG and CT scan to pick up NAFLD is only 85 – 90% and it is further low if steatosis is less than 30%. Liver biopsy remains the gold standard for diagnosis of NAFLD and distinguishing NAFLD from NASH. Histology of this patient is suggestive of NAFLD (Presence of steatosis, lobular infiltrate) but is not confirmatory of NASH in absence of ballooning degeneration, glycogenated nuclei, Mallory hyaline and fibrosis. However recent studies have highlighted the sampling error of liver biopsy in evaluation of NASH.

Despite a stepwise approach and detailed investigation a small proportion of patients may still remain undiagnosed. Rare causes like heterozygous hypobetalipoprotienemia characterized by low levels of triglycerides and LDL should be looked for in these patients.

Finally a regular follow up with avoidance of alcohol and hepatotoxic drugs with lifestyle modification would be prudent and essential to assess the implications of the persistent asymptomatic transaminasemia as in this case.

Recommended Reading:

American Gastroenterological Association. Medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002; 123:1364-6

Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002; 123:1367-84

Paul T. GIBONEY, “Mildly Elevated Liver Transaminase Levels in the Asymptomatic Patient”. Am Fam Physician, 2005;71:1105-10, (http:www.aafp.org/afp/20050315/1105.html)

Madan K. Batra Y, Panda SK, Dattagupta S. Hazari S, Jha JK, Acharya SK “Role of Polymerase chain reaction and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach”. J.Gastroenterol Hepatol. 2004 Nov; 19(11):1291-9.