1. Carmel Medical Center Clalit Health Services
ASSESEMENT OF ABNORMAL LIVER TESTS
Prof. Eli Zuckerman, M.D. Liver Unit Haifa and Western Galilee District and
Carmel Medical Center Clalit Health Services

2. Liver tests ALT ALT (GPT) AST (GOT) LDH ALP (alkaline phosphatase) GGT
bilirubin
albumin
P.T (prothrombin time)
globulin
CBC
AST, LDH

3. 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. non-cirrhotic)

4. Markers of Hepatocellular damage (Transaminases)
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

5. 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

6. 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

7. CLINICAL ASSESSMENT OF LIVER DISEASE SEVERITY
Physical examination (I)
Peripheral signs of CLD (“stigmata”):
• spider angiomata
• Dupuytren’s contracture
• palmar erythema
• testicular atrophy
• gynecomastia

8. 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

9. 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

10. Patterns of liver enzyme alteration
Hepatic vs cholestatic
Magnitude of enzyme alteration (ALT >10x vs minor abnormalities)
Rate of change
Nature of the course of the abnormality (mild fluctuation vs progressive increase)

11. CLINICAL ASSESSMENT OF LIVER DISEASE SEVERITY
Case 1.
ALT (GPT)
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin N
P.T (60%)
globulin
CBC N

12. Admission?

13. Differential diagnosis?

14. Acute hepatitis (ALT>10xULN)
Viral
Ischaemic
Toxins
Autoimmune
Acute Budd-Chiari
Early phase of acute obstruction
Metastatic liver-diffuse (extremely rare)

15. * Extremely high AST & LDH: ischemic, toxic
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, drug-
induced
* Alcoholic hepatitis: AST/ALT >1 (92%)
AST <300 (98%)

16. “Hit and Run” pattern of liver enzymes
AST
ALT

17. Diagnostic blood tests?

18. 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)

19. IgG 2430 mg/ml
anti-smooth muscle +++
ANA 1:160

20. Liver biopsy?

21. Interface hepatitis
Interface hepatitis. Here you can see the limiting plate of the portal tract, demarcating the hepatocyte boundary, is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis, but it is not disease specific.
Hematoxylin and eosin, *200.
Extra notes:
Acute onset AIH pattern: panancinar hepatitis that resembles an acute viral or drug-induced hepatitis.
Centrilobular or pervenular (rappaprot zone 3) hepaitits that resembles an acute toxic injury.

22. Lobular Hepatitis
Figure 75–2. Lobular hepatitis in which mononuclear inflammatory cells line the sinusoidal spaces. Typically, lobular hepatitis coexists with interface hepatitis, but it may be pronounced during acute onset or during relapse after treatment withdrawal. Hematoxylin and eosin, *200.

23. Plasma cell infiltration
Plasma cells are identified by their eccentric, clock-face nucleus, and pale perinuclear cytoplasm. There are not pathognomonic of the disease nor required for diagnosis.

24. Case 2. 28 y/o male, asymptomatic, BMI 27.7, • ALT (GPT) 132
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin N
CBC N
Cholesterol 277 (LDL-C 170)
TG 304

25. Differential diagnosis?

26. CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 2.
• D.D
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.

27. Diagnostic blood tests?

28. 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)

29. All diagnostic blood tests negative except anti-smooth muscle Ab ±

30. Imaging features
US sensitivity depends on hepatic fat content- >30% fat, sensitivity 80%
10-19% fat, sensitivity 55%
Morbid obesity – sensitivity 49%, specificity 75% 30

31. MANAGEMENT OF NAFLD • TO BIOPSY OR NOT TO BIOPSY ? • WHOM TO BIOPSY ?

32. NASH - RISK FACTORS FOR FIBROSIS AND CIRRHOSIS
Independent risk factors in several studies:
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

33. Case 3. 48 y/o male, asymptomatic, BMI 36 • ALT (GPT) 100
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin
PLT
Cholesterol 277 (LDL-C 170)
TG 304

34. HIT # 1

35. NAFLD-”simple” steatosis

36. NASH Fibrosis

37. NASH cirrhosis

38. Management?

39. Treatment of NAFLD 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 ? 39

40. Surgery 40

41. 41

43. Statins? Case 4. 61 y/o male, asymptomatic, BMI 27.7, • ALT (GPT) 87
IHD (PTCA + stent RCA), HTN, US: “fatty liver”
• ALT (GPT)
AST (GOT)
ALP
GGT
bilirubin
albumin
P.T
globulin N
CBC N
Cholesterol 277 (LDL-C 170)
TG 304
Statins?

44. After 12 weeks of Rx with statins
• ALT (GPT)
AST (GOT)
ALP
GGT
bilirubin
albumin
Cholesterol 210 (LDL-C 123)
TG 220

45. Continued treatment FOR THE PHYSICIAN 3. Fulminant hepatitis ALAT
2. Chronic
liver
disease
5 ULN
1. Adaptation
1 ULN
DRUG

46. Monreal, Eur J Clin Pharmacol
Black, Gastroenterology , 1975;69:289
0.1% Death
CLINICAL
1% Jaundice
INFRA-
CLINICAL
ALT > 10 ULN
Unfractionated
heparin
Isoniazid
30%  Transaminases
15%  Transaminases
Monreal, Eur J Clin Pharmacol
1989;37:415
Huang, Hepatology
2002;35:

53. Case 5. 28 y/o male, asymptomatic, BMI 27, • ALT (GPT) 132
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin N
CBC N
Cholesterol 177 (LDL-C 108), TG 120
HCV +

56. Case 6. 28 y/o male, asymptomatic, BMI 27, • ALT (GPT) 98
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T
globulin N
CBC N
HBsAg +
Next step ?

57. Case 6. 28 y/o male, asymptomatic,,
HBsAg +
HBeAg -
HBeAb +
HBcAb +
HDV -
HBV DNA (PCR) +
HBV DNA 2.8 X 104 IU/ml

58. New approaches to patient management strategy: HBV

59. HBV TREATMENT HBV DNA (viral load) Elevated ALT HBeAg status
Severity of liver disease

60. הפטיטיס B קריטריונים לטיפול
עומס נגיפי מעל 2,000 Iu/mL
רמת ALT > מ- ULN
ביופסיה עם עדות לפיברוזיס או שינויים נקרו-אינפלמטוריים משמעותיים

61. 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:

62. Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001
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

63. Other Liver biopsy Findings in Abnormal LFTs Skelly et al
Other Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001
Cryptogenic hepatitis 9%
Drug induced %
Alcoholic liver disease 2.8%
Autoimmune hepatitis 1.9%
PBC %
PSC %
Granulomatous disease 1.75%
Haemochromatosis 1%
Amyloid %
Glycogen storage disease 0.31%

64. LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL
N = 249, mean age 58, etoh < 25 units per week, 9% diabetes, 24% BMI > 27
ALT (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

65. LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL
Of those with NAFLD:
56% had simple steatosis
44% inflammation and/or fibrosis
Risk of Severe Fibrotic Disease associated with:
BMI >27
Gamma GT > 2x normal
Ryder et al BASL 2003

66. Abnormal LFTs - Conclusions
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

67. CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 7.
• ALT (GPT)
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin N
globulin
P.T
CBC N

68. • D.D ULTRASOUND (± CT): dilated vs. non- dilated ducts Case 7
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)

69. • anti-mitochondrial Ab +,
Case 6
• anti-mitochondrial Ab +,
IgM 330, IgG 1400
ANA +, anti-smooth muscle Ab -

72. CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 8
• ALT (GPT)
AST (GOT)
LDH
ALP
GGT
bilirubin
albumin N
globulin
P.T
CBC N

73. CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure)
AST (GOT)
ALT (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T (40%)
globulin N
CBC ,000

74. CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure)
AST (GOT)
ALT (GOT)
LDH
ALP
GGT
bilirubin
albumin
P.T (40%)
globulin N
CBC ,000
CPK

75. Thank you

76. THANK YOU Liver tests Slide 76. Predictability
This section will discuss the ability to predict SVR or nonresponse early in the course of treatment with PEGASYS® (peginterferon alfa-2a [40KD]).