ASYMPTOMATIC LFT ELEVATION

Cary Ostergaard MDCAPT,MC, USN

APRIL 2009

Introduction

• 45 year old white male here for a follow up visit. At the prior visit, he complained of fatigue. You order a CBC, TSH, and Chem everything. PMH includes obesity, hyperlipidemia, and pre-diabetes. He comes back today to review the results (which you looked at 30 seconds before going in the room).

• All normal except for ALT=88 and AST=59

Introduction

• Clinical approach to abnormal liver tests in the office setting. In line with the 2002 American Gastroenterology Association Guidelines

• Liver Function tests (LFT’s) is really a misnomer although we all use it

• Looking at 3 common, isolated findings– AST/ALT elevation– Alkaline Phosphatase elevation– Unconjugated bilirubin elevation

Epidemiology

• 57% of Family Physicians include liver function tests as part of routine lab screening

• Obesity epidemic will increase abnormal results

• The more tests you order the more likely you will get an abnormal result.

Probability of an abnormal screening test result

92 percent5064 percent2040 percent1026 percent619 percent410 percent25 percent1

Probability of abnormal test

Number of independent tests

Reproduced with permission from: Kaplan, MM. Approach to the patient with abnormal liver function tests. In: UpToDate, Basow,

DS (Ed), UpToDate, Waltham, MA, 2009

Case 1

• 45 year old white male here for a follow up visit. At the prior visit, he complained of fatigue. You order a CBC, TSH, and Chem 20. PMH includes obesity, hyperlipidemia, and pre-diabetes. He comes back today to review the results (which you looked at 30 seconds before going in the room).

• All normal except for ALT=88 and AST=59

Elevated AST/ALT (Transaminase)

• ALT is more liver specific than AST, but both can be found in other tissues such as muscle

• Degree of elevation does not always correlate with the severity of liver disease

• AST/ALT ratio may imply certain diagnosis, but to much overlap to rely on this ratio– Alcohol typically >2.0– Non Alcoholic Fatty Liver Disease (NAFLD) <1.0

Differential Diagnosis

• 1. Toxins: Alcohol, tylenol, statins, INH, epilepsy meds, high dose vitamin A, NSAIDS, supplements

• 2. Infections: Especially Hepatitis B&C• 3. NAFLD • 4. Miscellaneous/Metabolic: hemochromatosis,

Wilson’s disease, Autoimmune Hepatitis, Alpha-1- antitrypsin deficiency, Celiac Disease, thyroid disease

History

• Exposure to toxins: Include supplements• Prior hx of hepatitis (review chart/AHLTA)• Risk for viral hepatitis: IVDA, tattoo,

needle stick, multiple partners, blood transfusion

• Symptoms: icterus, fatigue, RUQ pain• FH of liver disease (especially

hemochromatosis)

PE

• Look for stigmata of chronic liver disease: spiders, palmar erythema, gynecomastia, testicular atrophy

• Look for hepatosplenomegally or ascites

Evaluation

• Step 1: History and PE looking for obvious cause

• Step 2. Repeat LFT’s in 2-4 weeks with avoidance of potential hepatotoxins

• Step 3. If still elevated – Fasting Labs: Lipids, FBS, iron, TIBC, ferritin,

HBsAg, HBsAb, HBcAb, HCV Ab, CBC, PT/PTT, Albumin

– Radiology: RUQ Ultrasound

Evaluation

• Step 4. Treat obvious causes.– Initial screening is looking for more common

conditions. – If no obvious cause and no evidence of hepatic

decompensation, monitor every 2-3 months.

Hepatitis B

• Further workup indicated if HBsAg positive• HBeAg, HBeAb, HBV DNA, HIV• If HBeAg or HBV DNA are positive,

would consider GI referral as they may need liver biopsy and/or treatment.

Hepatitis C

• Screening test is an Elisa antibody test. • If positive in the face of abnormal

transaminases, would get a HCV RNA load.• If HCV RNA is detectable, would

recommend GI referral for further evaluation and potential treatment.

Non-alcoholic Fatty Liver Disease

• Most common finding in liver biopsy when no other cause is identified.

• Histological features resemble alcohol induced liver disease

• Increasing with the obesity epidemic• Progression of steatosis to non-alcoholic

steatohepatitis (NASH), and can progress to cirrhosis

Non-alcoholic Fatty Liver DiseaseTreatment

• Lifestyle changes• Statin:

– Safe to use – Would not start if Transaminases are more than

3X upper limit of normal (ULN)– Recheck LFT’s in 2 weeks then every month

for 3 months– Stop if transaminases increase more than 2-3X

above baseline

Non-alcoholic Fatty Liver DiseaseTreatment

• Insulin Sensitizers– Metformin safe to use

• Key is the treatments have only been proven to improve disease oriented outcomes (steatosis and abnormal tranasminases). No proven affect on patient oriented outcomes such as morbidity and mortality.

• Recommend they be used for normal indications pending further studies

Hereditary Hemochromatosis

• Most common in patients of Northern European descent– 1 in 10 Caucasians in the U.S. are heterozygote

• Genetic testing available• Diagnosis:

– Fasting Iron saturation >50% (some references use >45%)

– Ferritin > 500 can also be suggestive– Genetic testing by looking at the HFE gene mutation– Liver biopsy may be needed

HereditaryHemochromatosis

• HFE Gene Mutation– C282Y most important in U.S. – 1:200 caucasians in U.S. are homozygous for

C282Y– Does not have complete penetrance– H63D the other common mutation– Can have Hemochromatosis without one of

these gene defects

Evaluation cont.

Step 5. If persistent elevation after 6 months, now it is considered chronic. Further evaluation to look for unusual causes.– Labs: Ceruloplasmin, SPEP, ANA, Anti

smooth muscle antibody (ASMA), Alpha-1 Antitrypsin, Tissue Transglutaminase (IGG and IGA), TSH, CK

Unusual Causes

• Wilson’s Disease• Autoimmune Hepatitis• Alpha-1-antitrypsin deficiency• Celiac Disease• Thyroid disease• Muscle source of AST

Wilson’s Disease

• Genetic defect in biliary copper excretion• Clinical onset age 5-25. Autosomal recessive• Rare if over 40 years of age• Diagnosis:

– Serum Ceruloplasmin (reduced in 85%)– Ophthalmology evaluation for Kayser-Fleischer rings– 24 hour urine for quantitative copper excretion (>100

micrograms)

Autoimmune Hepatitis

• Type 1: Most common in U.S. Associated with ANA and ASMA

• Type 2: Rare in U.S. Anti-liver-kidney microsomal antibody (anti-LKM)

• Female:Male 4:1• Diagnosis:

– SPEP (polyclonal gammopathy 80% sensitive)– ANA (30% sensitive)– ASMA(40% sensitive)

Alpha-1 Antitrypsin Deficiency

• 10-15% have liver damage• Again more common in those of Northern

European descent• Look for lung disease• Diagnosis:

– Low level of Alpha-1 Antitrypsin (can be elevated in the face of inflammation creating false negative result)

Celiac Disease

• Mostly Caucasians of Northern European ancestry• At one referral center, accounted for 10% of

otherwise unexplained elevations in transaminases• Diagnosis:

– Screen with tissue transglutaminase (IgG and IgA)– Definitive diagnosis by small bowel biopsy

Muscle Source

• Often have other symptoms or findings such as myalgia, weakness, muscle wasting.

• Diagnosis:– CK

Consultation

• Step 6: No obvious cause and no evidence hepatic decompensation– If still elevated (especially if AST and ALT

greater than 2 X ULN), consider GI consult for potential liver biopsy.

– If less than 2X ULN and no evidence obvious cause, appropriate to follow.

Case 1

• Initial evaluation was normal except for elevated lipids and FBS of 122.

• US consistent with Fatty liver

Case 2

• 63 yo female s/p gastric bypass 3 years prior. Complaining of epigastric discomfort. All labs normal except for alkaline phosphatase which is 330. Rest of LFT’s are normal.

ELEVATED ALKALINE PHOSPHATASE

• Multiple sources: liver, bone, placenta, intestine, neoplasm

• Make sure it is not physiological (pregnancy, child, postprandial)

• Bone and hepatobiliary most common cause of significant elevation

• Get GGT to determine origin

ELEVATED ALKALINE PHOSPHATASE

• Step 1: Repeat fasting Alkaline Phosphatase along with GGT

• Step 2: Workup dependent on whether it is hepatobiliary in origin (elevated GGT) or bone source (GGT normal)

GGT Normal

• Most likely bone source• DDX: Paget's, Hyperthyroidism,

Hyperparathyroidism, Rickets, Healing Fracture, Malignancy

• Labs: Chem 7, Ca, PO4, TSH, PTH, SPEP• Radiology: Bone Scan

GGT Elevated

• Hepatobiliary source• DDX: Cholestasis, infiltrative disease• Labs: Antimitochondrial Antibody (AMA)• Radiology: RUQ US

ELEVATED ALKALINE PHOSPHATASE

• Step 3: Appropriate workup for abnormal results. If no obvious cause:– Monitor labs every 2-3 months– If still elevated at 6 months, hepatobiliary in

origin, and >1.5 times upper limit of normal, refer to GI for possible liver biopsy.

Case 2

• Patient had an elevated PTH and low Ca++ consistent with secondary hyperparathyroidism.

Case 3

• 23 yo AD male. Seen in clinic for N/V/D and mild abdominal pain. Exam shows mild dehydration. Only remarkable labs are Tbili=2.8 and D bili = 0.2.

ELEVATED BILIRUBIN

• Step 1: – Determining conjugated (direct) vs

unconjugated (indirect) first step– Always obtain a direct bilirubin level

• Step 2: Workup dependent on whether it is conjugated or unconjugated

Elevated unconjugated bilirubin and normal Alk Phos/AST/ALT

• DDX includes hemolysis, enzyme deficiency (Gilbert’s) and medications

• Labs: CBC and reticulocyte count• If they are normal, most likely Gilbert’s

disease• If still consideration of hemolysis, get a

haptoglobulin level which will be decreased with hemolysis

Case 3

• CBC and reticulocyte count were normal• Bilirubin normal at follow up• Diagnosed with Gilbert’s

– Up to 5% of the population has Gilbert’s

Questions????

REFERENCES

• Giboney PT. Mildly Elevated Liver Tranasminase Levels in the Asymptomatic Patient. AFP 2005 Mar 15;71(6):1105-10.

• Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000;342:1266-71.

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

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