Chronic Transaminitis

Dr. Danny Panisko

UHN/MSH AIMGP Seminar Series
March 2007

Chronic Transaminitis: Objectives

At the end of this seminar you will be able to:
Define chronic transaminitis
List an underlying differential diagnosis
Understand relevant features on History
Conduct a relevant Physical Exam
Describe a guideline-based Investigation
approach

Chronic Transaminitis: Outline

Objectives/Outline and Guidelines/References

Cases
Differential Diagnosis
Medical History
Physical Examination
Initial Laboratory Evaluation
Diagnostic Algorithm
Revisit Objectives

Chronic Transaminitis:
Guidelines

AGA Medical Position Statement: Evaluation of Liver Chemistry Tests.

Gastroenterology 2002; 123: 1364-66. Also available at
www.gastro.org

AGA Technical Review on the Evaluation of Liver Chemistry Tests.

Gastroenterology 2002; 123: 1367-84. At www.gastro.org

National Academy of Clinical Biochemistrys Laboratory Guidelines for

the Screening, Diagnosis, and Monitoring of Hepatic Injury 2000;
Section 4; Chronic Hepatic Injury; pp.31-8. At www.nacb.org

Chronic Transaminitis:
Useful References

Pratt DS and Kaplan MM. Evaluation of abnormal liver-enzyme results

in asymptomatic patients. N Eng J Med 2000; 342: 1266-71

Role of PCR and liver biopsy in the evaluation of patients with

asymptomatic transaminitis: implications in diagnostic approach. J
Gastroenterol Hepatol 2004; 19(11): 1291-9

ONeil J and Powell L. Clinical aspects of hemochromatosis. Sem

Liver Dis 2005; 25(4): 381-91

Giannini EG et al. Liver enzyme alteration: A guide for clinicians.

CMAJ 2005; 172: 367-79

Chronic Transaminitis: Cases

Ms. A. Viral, Miss B. Immune, and Mrs. C. Metaltoxin are three

asymptomatic 35 year old women coincidently referred to your
AIMGP clinic on the same day.

They were noted to have elevated transaminases (AST 100-125,

ALT 100-125 [N<35]; and N ALP and Tbili) by their family MDs on
routine bloodwork 6 months ago. Repeat bloodwork, miraculously
performed on the same day, revealed similar values 2 months ago
and also one week ago.

The women have been well with no symptoms. They look

surprisingly similar to you maybe identical triplets lost at birth !

Chronic Transaminitis: Cases

Do these mysterious women have chronic

transaminitis?

Chronic Transaminitis: Cases

Do these mysterious women have chronic

transaminitis?
Yes. This entity is defined as persistence of
elevated ALT for more than 6 months, either
after an episode of acute hepatitis or without
another explanation.

Chronic Transaminitis: Cases

Why is the time frame of 6 months important ?

In general terms, what is the sensitivity this definition for

chronic hepatic injury ?

Chronic Transaminitis: Cases

Why is the time frame of 6 months important ?

It defines a clinical entity with a limited differential and
eliminates a variety of short-lived causes of liver injury that
do not have long term consequences or considerations.
Work up of mild asymptomatic transaminitis that does not
persist is not indicated in a patient without risk factors.
Work up of chronic asymptomatic transaminitis is
conducted in the hope of preventing progression to
cirrhosis.

Cirrhosis:

Chronic Transaminitis: Cases

In general terms, what is the sensitivity of this definition

for chronic hepatic injury ?
While generally sensitive and specific, it is not perfect.
For example, some patients with chronic Hepatitis C
infection do not mount elevated ALTs.
Also, a patient with primary biliary cirrhosis or sclerosing
cholangitis may only have an elevated ALP earlier in the
course of their disease.

Chronic Transaminitis: Dxdx

In terms of broad disease categories, what is a

differential diagnosis of potential etiologies of
chronic transaminitis ?

Chronic Transaminitis: Dxdx

In terms of broad disease categories, what is a differential

diagnosis of potential etiologies of chronic transaminitis ?

Viral
Immune
Metal deposition / Toxic
Other including non-hepatic !
Can you provide more detail for this differential before
viewing the answers on the next slide?

Chronic Transaminitis: Dxdx

Which medications, herbs, street drugs can lead

to transaminitis and liver injury ?

(Note: chronic recurrent use can lead to chronic

liver injury)

Chronic Transaminitis: Dxdx

Which Immune causes of liver disease can lead

to chronic transaminitis ?

Chronic Transaminitis: Dxdx

Which Immune causes of liver disease can lead

to chronic transaminitis ?
True Auto-immune hepatitis
Primary Biliary Cirrhosis
Sclerosing Cholangitis

Chronic Transaminitis: History

Given the previously discussed differential

diagnosis, what are important historical features
to explore in a patient with chronic transaminitis ?

Chronic Transaminitis: History

Symptoms of liver injury: fatigue, weakness, icterus,

pruritis, dark urine, possible stool colour lightening,
nausea, vomiting, RUQ discomfort, intolerance to dietary
protein or cigarette smoke

Symptoms of the consequences of cirrhosis: bleeding,

cachexia, edema, ascites, encephalopathy, skin changes,
gynecomastia etc.

Chronic Transaminitis: History

Risk factors / etiology:

fecal/oral and blood/body fluid exchange risks for

viral hepatitis
drugs, medications, herbs, toxins, alcohol [CAGE],
acetaminophen (primary or co-toxin)
obesity, dieting, obesity surgery, bullemia, diabetes as
risks for non-alcoholic steatohepatitis (NASH)
Family history: for diseases with symptoms
consistent for hemochromatosis, Wilsons, alpha-1
antitrypsin, or autoimmune

Chronic Transaminitis: Physical

What physical exam features should be

emphasized in a patient with chronic
transaminitis ?
(Can you identify the physical signs on the following slides ?)

Chronic Transaminitis: Physical

Obviously trivia..
Dermatitis herpetiformis: chronic herpetiform lesions on
extensor surfaces (in this case, elbows) in patients with
Celiac Disease
Kayser-Fleischer Rings, best appreciated with a slit
lamp, as brown pigmentary deposits on the periphery of
the cornea, in patients with Wilsons disease
Tendon xanthomata, on the Achilles, in patients with
hyperlipidemia due to cholestasis in liver disease that
also can have chronic transaminitis such as primary
biliary cirrhosis

Chronic Transaminitis: Physical

Findings of liver injury and structural change:

hepatomegaly, RUQ tenderness
Findings of liver dysfunction: icterus/jaundice, edema,
bleeding, bruising, edema, encephalopathy, asterixis,
fetor hepaticus
Findings of portal hypertension: splenomegaly, caput
medusa, hemorrhoids, ascites
Stigmata of chronic liver disease
Findings of Etiologic disease processes: bronze
diabetes, mental status changes/psychoses,
malnutrition/malabsorption, vasculitic purpura (what are
the connections with these signs ?)

Chronic Transaminitis:
Case History and Physical

No additional history or physical exam data was

contributory for none of the suspiciously similar Ms.
A. Viral, Miss B. Immune, nor Mrs. C. Metaltoxin.
except that Ms. A. Viral received a transfusion of
2 units of pRBCs after a car accident in 1986,
and Mrs. C. Metaltoxin underwent a total
hysterectomy because of fibroids at age 30

Chronic Transaminitis: Initial Labs

What are considered relevant initial laboratory

investigations by several expert consensus
guidelines ?

Chronic Transaminitis: Initial Labs

What are considered relevant initial laboratory

investigations for chronic transaminitis by
several expert consensus guidelines ?
Liver enzymes, INR, Albumin, CBC with
platelets, Hepatitis B S Ag, Hepatitis B S Ab,
Hepatitis C IgG, % Iron Saturation and/or Ferritin

Chronic Transaminitis: Initial Labs

Ms. A. Viral was found to have Hepatitis C IgG

positive. Therefore, a diagnosis of Chronic Hepatitis
C was made. She was referred to a hepatologist for
consideration of antiviral therapy.

Mrs. C. Metaltoxin was found to have an iron

saturation of 58% (n<45%) and a ferritin of 850 mcg/l
(n = 22-322)

What is her diagnosis ?

Does she need further diagnostic testing ?
What are the broad principles in her management ?

Chronic Transaminitis:
Mrs. C. Metaltoxin

She likely has hereditary hemochromatosis, was not on iron

supplements, & did not take alcohol to excess (why is this relevant ?)

Some physicians like to confirm the degree of iron overload definitively

with liver biopsy

She and her first degree relatives should receive genetic screening,
with HFE mutation analysis, to facilitate decision making for treatment
of family members and genetic counseling

Treat with phlebotomy get Fe saturation below 50%, & assess for
cirrhosis and other systemic involvement of Fe overload

Chronic Transaminitis:
Diagnostic Algorithm

Miss B. Immune had (N) initial investigations

apart from a repeat of the transaminases which
were minimally elevated as before

What should be done now ?

Chronic Transaminitis:
Diagnostic Algorithm

The AGA algorithm suggests abdominal ultrasound,

ANA, Ceruloplasmin, anti-smooth muscle antibody, antigliadin antibody, anti-endomysial antibodies and alpha-1
antitrypsin level.
(What entities do these investigations test for ?
see answer on next slide)

The algorithm also suggests further confirmatory liver

biopsy if any of these results are abnormal. Many
hepatologists would also do a liver biopsy at this point if
there was still no diagnosis.
(See algorithm on 2nd slide following)

Chronic Transaminitis:
Miss B. Immune

Miss B. Immune had a positive ANA at a titre of

1:640.

A liver biopsy confirmed autoimmune hepatitis

with no evidence of cirrhosis.

She was referred to a hepatologist and started

on Prednisone therapy.

Chronic Transaminitis: Objectives

Hopefully, you are now able to:
Define chronic transaminitis
List an underlying differential diagnosis
Understand relevant features on History
Conduct a relevant Physical Exam
Describe a guideline-based Investigation
approach