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.
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.
he was found to have a just palpable non-tender
liver with no stigmata of chronic liver disease.
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
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.
|HBsAg /Anti HCV
|Total Anti HBc
|24 hrs Urinary copper
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.
|Waist : Hip
||32 : 38
||30 : 38
|Blood Sugar (F)
|Insulin level (F)
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.
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.
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.
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
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.
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
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.
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
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