Transcript Evaluation of Abnormal Liver Function Tests

ASSESEMENT OF ABNORMAL LIVER TESTS
Prof. Eli Zuckerman, M.D.
Liver Unit
Haifa and Western Galilee District and
Carmel Medical Center
Clalit Health Services
Liver tests
ALT
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ALT (GPT)
AST, LDH
AST (GOT)
LDH
ALP (alkaline phosphatase)
GGT
bilirubin
albumin
P.T
(prothrombin time)
globulin
CBC
CLINICAL ASSESSMENT OF ABNORMAL LIVER
TESTS
Blood tests
• Acute/recent vs. chronic liver disease
• Hepatocellular vs. cholestatic injury
• Etiology of liver disease (ALD, viral…)
• Severity of liver disease (cirrhotic vs. noncirrhotic)
Markers of Hepatocellular damage
(Transaminases)
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AST- liver, heart skeletal muscle, kidneys, brain,
RBCs
In liver 20% activity is cytosolic and 80% mitochondrial
Clearance performed by sinusoidal cells, half-life
17hrs
ALT – more specific to liver, v.low concentrations in
kidney and skeletal muscles.
In liver totally cytosolic.
Half-life 47hrs
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Gamma-GT – hepatocytes and biliary epithelial
cells, pancreas, renal tubules and intestine
Very sensitive but Non-specific
Raised in ANY liver disease hepatocellular or
cholestatic
Usefulness limited
Confirm hepatic source for a raised ALP
Alcohol
Isolated increase does not require any further
evaluation, suggest watch and rpt 3/12 only if other
LFT’s become abnormal then investigate
Markers of Cholestasis
ALP – liver and bone (placenta, kidneys,
intestines)
 Hepatic ALP present on surface of bile duct
epithelia and accumulating bile salts increase
its release from cell surface. Takes time for
induction of enzyme levels so may not be first
enzyme to rise and half-life is 1 week.
 ALP isoenzymes, 5-NT or gamma GT may be
necessary to evaluate the origin of ALP
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CLINICAL ASSESSMENT OF LIVER DISEASE
SEVERITY
Physical examination (I)
Peripheral signs of CLD (“stigmata”):
• spider angiomata
• Dupuytren’s contracture
• palmar erythema
• testicular atrophy
• gynecomastia
Physical examination (II)
Significant liver disease and/or portal HTN
• Enlarged Lt. Lobe
• Firm liver (fibrosis/cirrhosis)
• Abdominal collaterals (portal HTN)
• Splenomegaly (portal HTN)
• Ascites
(high SAAG, portal HTN)
• Muscle wasting
Bilirubin, Albumin and Prothrombin
time (INR)
Useful indicators of liver synthetic
function
 In primary care when associated with
liver disease abnormalities should
raise concern
 Thrombocytopenia is a sensitive
indicator of liver fibrosis
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Patterns of liver enzyme alteration
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Hepatic vs cholestatic
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Magnitude of enzyme alteration (ALT >10x
vs minor abnormalities)
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Rate of change
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Nature of the course of the abnormality (mild
fluctuation vs progressive increase)
CLINICAL ASSESSMENT OF LIVER DISEASE
SEVERITY
Case 1.
ALT (GPT)
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin
CBC
1890
1750
880
180
170
1.0
N
1.4 (60%)
4.3
N
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Admission?
Differential
diagnosis?
Acute hepatitis (ALT>10xULN)
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Viral
Ischaemic
Toxins
Autoimmune
Acute Budd-Chiari
Early phase of acute obstruction
Metastatic liver-diffuse (extremely rare)
Comments
* Extremely high AST & LDH: ischemic, toxic
(paracetamol, ecstasy)
* “Hit and run” pattern: (AST 17h, ALT 47h):
ischemic, toxic, CBD stone
* Relatively preserved appetite: AIH, druginduced
* Alcoholic hepatitis: AST/ALT >1 (92%)
AST <300 (98%)
“Hit and Run” pattern of liver enzymes
AST
ALT
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Diagnostic blood tests?
Diagnostic tests: acute hepatitis
* HAV-IgM, HBsAg, HBc-IgM, HCV (± HCV RNA)
* Anti smooth muscle Ab, ANA, anti-LKM-1
* Ultrasound
* CMV-IgM, EBV-IgM
* Additional: toxic screen, Doppler US (hepatic
veins)
 IgG 2430 mg/ml
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anti-smooth muscle +++
 ANA 1:160
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Liver biopsy?
Interface hepatitis
Lobular Hepatitis
Plasma cell infiltration
Case 2. 28 y/o male, asymptomatic, BMI 27.7,
• ALT
(GPT)
132
AST (GOT)
51
 LDH
467
 ALP
66
 GGT
95
 bilirubin
0.6
 albumin
4.3
 P.T
1.1
 globulin
N
 CBC
N
 Cholesterol 277 (LDL-C 170)
 TG 304
Differential
diagnosis?
CLINICAL ASSESSMENT OF ABNORMAL LIVER
TESTS
Case 2.
• D.D
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Fatty liver or NASH (non alcoholic steatohepatitis)
(DM II, HLP, obesity, insulin resistance)
 Chronic viral hepatitis (HBV, HCV)
 Alcoholic liver disease (AST>ALT, MCV , GGT )
 Autoimmune hepatitis (ANA, aSMA, LKM-1)
 Wison’s disease (age < 55) (hemochromatosis, A1AT)
 Drug induced liver injury
 Celiac disease, Addison.
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Diagnostic blood tests?
Diagnostic tests case 2: asymptomatic
abnormal LT (X2-5)
* Viral serology: HBsAg, HCV (± HCV RNA)
* Autoimmune screen: anti-smooth muscle Ab,
ANA, anti-LKM-1, (anti mitochondrial)
* Metabolic (age < 50): ceruloplasmin, ferritin,
transferin, iron, α1 anti-trypsin
* NAFLD: lipids, HbA1c, insulin resistance, glucose
* US
* Additional: celiac (anti-transglutaminase, endomysial)
 All diagnostic blood tests negative
except anti-smooth muscle Ab ±
Imaging features
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US sensitivity depends
on hepatic fat content>30% fat, sensitivity
80%
10-19% fat, sensitivity
55%
Morbid obesity –
sensitivity 49%,
specificity 75%
MANAGEMENT OF NAFLD
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TO BIOPSY OR NOT TO BIOPSY ?
WHOM TO BIOPSY ?
NASH - RISK FACTORS FOR FIBROSIS AND
CIRRHOSIS
Independent risk factors in several studies:
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Age >45
ALT > 2x normal
AST/ALT ratio > 1
Obesity, particularly truncal , BMI > 27
Type 2 diabetes
Insulin Resistance
Hyperlipdemia (trigycerides > X1.7)
NB: Studies are in selected groups; may not apply to all patients
Case 3. 48 y/o male, asymptomatic, BMI 36
• ALT
(GPT)
100
AST (GOT) 125
 LDH
467
 ALP
66
 GGT
95
 bilirubin
0.6
 albumin
3.7
 P.T
1.1
 globulin
4.0
 PLT
138000
 Cholesterol 277 (LDL-C 170)
 TG 304
HIT # 1
NAFLD-”simple” steatosis
NASH Fibrosis
NASH cirrhosis
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Management?
Treatment of NAFLD
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Weight reduction Diet + exercise*
Pharmacological: orlistat,
Bariatric surgery *
 Insulin sensitizing agents thioglitazones * (pio-, rosi-)
metformin *
 Anti-oxidants
Vit E, betain
 Cytoprotective
Ursodeoxicholic acid
 Lipid lowering agents
HMG-CoA RI’s ?
Fibrates ?
Surgery
Case 4. 61 y/o male, asymptomatic, BMI 27.7,
IHD (PTCA + stent RCA), HTN, US: “fatty liver”
• ALT
(GPT)
87
AST (GOT) 51
 ALP
66
 GGT
95
 bilirubin
0.6
 albumin
4.3
 P.T
1.1
 globulin
N
 CBC
N
 Cholesterol 277 (LDL-C 170)
 TG 304
Statins?
After 12 weeks of Rx with statins
• ALT
(GPT)
220
AST (GOT) 110
 ALP
100
 GGT
95
 bilirubin
1.0
 albumin
4.3
 Cholesterol 210 (LDL-C 123)
 TG 220
FOR THE PHYSICIAN
Continued treatment
ALAT
3. Fulminant
hepatitis
2. Chronic
liver
disease
5 ULN
1. Adaptation
1 ULN
DRUG
Black, Gastroenterology , 1975;69:289
CLINICAL
0.1% Death
1% Jaundice
INFRACLINICAL
ALT > 10 ULN
Unfractionated
heparin
Isoniazid
30%  Transaminases 15%  Transaminases
Monreal, Eur J Clin Pharmacol
1989;37:415
Huang, Hepatology
2002;35:883-889
Case 5. 28 y/o male, asymptomatic, BMI 27,
• ALT
(GPT)
132
AST (GOT)
51
 LDH
467
 ALP
66
 GGT
95
 bilirubin
0.6
 albumin
4.3
 P.T
1.1
 globulin
N
 CBC
N
 Cholesterol 177 (LDL-C 108), TG 120
 HCV +
Case 6. 28 y/o male, asymptomatic, BMI 27,
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ALT (GPT)
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin
CBC
HBsAg +
98
51
467
66
95
0.6
4.3
1.1
N
N
Next step ?
Case 6. 28 y/o male, asymptomatic,,
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HBsAg +
HBeAg HBeAb +
HBcAb +
HDV HBV DNA (PCR) +
HBV DNA 2.8 X 104 IU/ml
New approaches to patient
management strategy: HBV
HBV TREATMENT
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HBV DNA (viral load)
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Elevated ALT
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HBeAg status
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Severity of liver disease
‫‪B‬הפטיטיס‬
‫קריטריונים לטיפול‬
‫‪ ‬עומס נגיפי מעל ‪Iu/mL 2,000‬‬
‫‪ ‬רמת ‪ > ALT‬מ‪ULN -‬‬
‫‪ ‬ביופסיה עם עדות לפיברוזיס או שינויים‬
‫נקרו‪-‬אינפלמטוריים משמעותיים‬
Liver biopsy Findings in
Abnormal LFTs
Skelly et al:
 354 Asymptomatic patients
 Transaminases persistently 2X normal
 No risk factors for liver disease
 Alcohol intake < 21 units/week
 Viral and autoimmune markers negative
 Iron studies normal
Skelly et al. J Hepatol 2001; 35: 195-294
Liver biopsy Findings in Abnormal
LFTs Skelly et al. J Hepatol 2001
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6% Normal
26% Fibrosis
6% Cirrhosis
34% NASH (11% of which had bridging
fibrosis and 8% cirrhosis)
32% Simple Fatty Liver
18% Alteration in Management
3 Families entered into screening
programmes
Other Liver biopsy Findings in
Abnormal LFTs Skelly et al. J Hepatol 2001
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Cryptogenic hepatitis
Drug induced
Alcoholic liver disease
Autoimmune hepatitis
PBC
PSC
Granulomatous disease
Haemochromatosis
Amyloid
Glycogen storage disease
9%
7.6%
2.8%
1.9%
1.4%
1.1%
1.75%
1%
0.3%
0.31%
LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL
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N = 249, mean age 58, etoh < 25 units per
week, 9% diabetes, 24% BMI > 27
ALT 51-99 (over 6 m)
72% NAFLD
10% Normal histologically
Others: Granulomatous liver disease 4%,
Autoimmune 2.7%, cryptogenic hepatitis 2.5%,
ALD 1.4%, metabolic 2.1%, biliary 1.8%
Ryder et al BASL 2003
LIVER BIOPSY FOR SERONEGATIVE
ALT < 2X NORMAL
Of those with NAFLD:
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56% had simple steatosis
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44% inflammation and/or fibrosis
Risk of Severe Fibrotic Disease associated
with:
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BMI >27
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Gamma GT > 2x normal
Ryder et al BASL 2003
Abnormal LFTs - Conclusions
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Many abnormal LFTs will return to normal
spontaneously
 An important minority of patients with
abnormal LFTs will have important
diagnoses, including communicable and
potentially life threatening diseases
 Investigation requires clinical assessment
and should be timely and pragmatic
CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 7.
• ALT (GPT)
AST (GOT)
 LDH
 ALP
 GGT
 bilirubin
 albumin
 globulin
 P.T
 CBC
48
52
214
348
488
1.0
N
3.2
0.8
N
Case 7
• D.D
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ULTRASOUND (± CT): dilated vs. nondilated ducts
 PBC
(anti-mitochondrial Ab, IgM)
 PSC
(IBD-UC, ANCA, ERCP, MRCP)
 Infiltrative disease (neoplastic, amyloidosis )
 Granulomatous disease (sarcoidosis, TB, Q fever)
 Granulomatous hepatitis
 Drug induced cholestatic liver injury (ACE-I, NSAIDs)
 Fatty liver (GGT-DM).
 Extra-hepatic obstruction (stones, neoplasm, stricture)
Case 6
• anti-mitochondrial Ab +,
IgM 330, IgG 1400
 ANA +, anti-smooth muscle Ab -
CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 8
• ALT (GPT)
AST (GOT)
 LDH
 ALP
 GGT
 bilirubin
 albumin
 globulin
 P.T
 CBC
24
37
214
100
112
1.0
N
3.2
0.8
N
CLINICAL ASSESSMENT OF ABNORMAL LIVER
TESTS
Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure)
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AST (GOT)
ALT (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin
CBC
7800
2500
8900
125
69
5.2
3.4
1.7 (40%)
N
18,000
CLINICAL ASSESSMENT OF ABNORMAL LIVER
TESTS
Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure)
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AST (GOT)
ALT (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin
CBC
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CPK
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7800
2500
8900
125
69
5.2
3.4
1.7 (40%)
N
18,000
23000
Liver tests