1. Approach to the patient with abnormal liver function tests
Dr. Davoodabadi
internist

2. "liver function tests" (LFTs)
Enzyme tests
Serum aminotransferases
Alkaline phosphatase
Gamma glutamyl transpeptidase
Tests of synthetic function
Serum albumin concentration
Prothrombin time
Serum bilirubin

3. Aminotransferases: Alanine aminotransferase (ALT = SGPT)
more specific indicator of liver injury
Aspartate aminotransferase (AST = SGOT)
liver
cardiac muscle
skeletal muscle
kidneys
brain
pancreas
Lungs
Leukocytes
erythrocytes

4. EPIDEMIOLOGY 
Abnormal LFTs are frequently detected in asymptomatic patients since many screening test panels now routinely include them .

5. A population-based survey in the United States conducted between 1999 and 2002
abnormal ALT was present in 8.9 %
increase in obesity during this same time period.
The serum ALT level correlates :
body mass index (BMI)
waist circumference

6. Abnormal serum aminotransferase levels (ALT >55 int
Abnormal serum aminotransferase levels (ALT >55 int. unit/L)  99 of 19,877 (0.5 percent]
known cause : only 12 patients (including chronic hepatitis B and C, autoimmune hepatitis, and cholelithiasis).
No specific diagnosis :87 patients.

7. A study of 1118 adult primary care patients in the United Kingdom.
Nonalcoholic fatty liver disease was the most common diagnosis (26 percent)
alcoholic liver disease (25 percent)
unexplained (45 percent) despite an evaluation that included ultrasonography and tests for viral, genetic, and autoimmune causes.

8. A study focused on 81 of 1124 patients with abnormal serum aminotransferase levels in whom a diagnosis could not be inferred noninvasively .
liver biopsy :
steatosis or steatohepatitis in the majority of patients (84 percent);
6 patients had fibrosis or cirrhosis,
8 patients normal histologic findings

9. HISTORY Important considerations include: any chemical or medication:
prescription drugs
over-the-counter medications
herbal drugs
The duration of LFT abnormalities
The presence of any accompanying symptoms:
jaundice, arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the color of urine and stool

10. Parenteral exposures :
transfusions
intravenous and intranasal drug use
tattoos
sexual activity

11. Other important questions :
recent travel history
exposure to people with jaundice
exposure to possibly contaminated foods
occupational exposure to hepatotoxins
alcohol consumption

12. PHYSICAL EXAMINATION Longstanding disease:
Temporal and proximal muscle wasting
Stigmata of chronic liver disease:
spider nevi
palmar erythema
gynecomastia
caput medusae

13. PHYSICAL EXAMINATION Laennec's cirrhosis : abdominal malignancy :
Dupuytren's contractures
Parotid gland enlargement
Testicular atrophy
abdominal malignancy :
Left supraclavicular node (Virchow's node)
Periumbilical nodule (Sister Mary Joseph's nodule)
Increased jugular venous pressure, a sign of right-sided heart failure, suggests hepatic congestion

14. ABDOMINAL EXAMINATION
Size and consistency of the liver
Size of the spleen (a palpable spleen is enlarged)
Assessment for ascites
fluid wave
shifting dullness
bulging of the flanks
Cirrhosis Patients :
enlarged left lobe of the liver (which can be felt below the xiphoid)
enlarged spleen

15. ABDOMINAL EXAMINATION
An enlarged tender liver:
Viral or alcoholic hepatitis
Acutely congested liver secondary to right-sided heart failure
Murphy's sign:
cholecystitis
ascending cholangitis
Ascites in the presence of jaundice :
cirrhosis
malignancy with peritoneal spread

16. LABORATORY TESTING 
A pattern predominantly reflecting hepatocellular injury
A pattern predominantly reflecting cholestasis

17. The SERUM BILIRUBIN can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two

18. Assess liver function :
The serum albumin level
prothrombin time(PT)
A low albumin :
chronic process such as cirrhosis or cancer
Normal albumin :
acute process such as viral hepatitis or choledocholithiasis

19. PT A prolonged prothrombin time :
vitamin K deficiency due to prolonged jaundice and intestinal malabsorption of vitamin K or significant hepatocellular dysfunction.
The failure of the prothrombin time to correct with parenteral administration of vitamin K :
severe hepatocellular injury

20. MILD CHRONIC ELEVATION IN SERUM AMINOTRANSFERASES
chronic :defined as six months or greater
mild elevation :defined approximately as less than five times the upper limit of normal

21. Step one Medications Supplements Alcohol use Viral hepatitis B and C
Hemochromatosis
Fatty liver

22. Medications Common causes: nonsteroidal anti-inflammatory drugs
antibiotics
statins
acetaminophen
antiepileptic drugs
antituberculous drugs
herbal preparations
illicit drugs

23. ACETAMINOPHEN
transient aminotransferase elevation among healthy adults even when taken in recommended doses.
In a study of healthy volunteers taking acetaminophen (4 g daily for 14 days), about 20 percent experienced an ALT elevation more than five times the upper limit of normal
An increase of 1 to 2 times the upper limit of normal was observed in 50 to 70 percent of patients
Elevation was not observed before three days of administration and generally resolved despite continued use of acetaminophen.

24. Alcohol abuse Dx of alcoholic liver disease: Other causes:
AST to ALT ratio of 2:1 or greater
Other causes:
nonalcoholic steatohepatitis
hepatitis C who have developed cirrhosis

25. other patterns of laboratory abnormalities of alcoholic liver disease:
1-A twofold elevation of the GGT in patients whose AST to ALT ratio is greater than 2:1 strongly suggests alcohol abuse.
2-It is rare for the AST to be greater than eightfold elevated and even less common for the ALT to be greater than fivefold elevated.
3-The ALT may even be normal even in patients with severe alcoholic liver disease

26. Hepatitis B
The proper initial testing for patients suspected of having chronic hepatitis B includes:
Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antibody (anti-HBs)
Hepatitis B core antibody (anti-HBc)

27. Hepatitis C Risk factors: Dx: hepatitis C antibody blood transfusions
intravenous drug use
occupational
cocaine use
tattoos
high risk sexual behavior
Dx: hepatitis C antibody
if positive : hepatitis C viral RNA

28. Hemochromatosis Hemochromatosis is a common genetic disorder.
HFEgene mutation C282Y
heterozygotes 10 percent
homozygous state 0.5 percent
Screening :
serum iron
total iron binding capacity (TIBC)
transferrin saturation (serum iron/TIBC)
Dx:
If transferrin saturation >45 percent -----serum ferritin.
ferritin >400 ng/mL in men
ferritin >300 ng/mL in women.

29. Nonalcoholic fatty liver disease and Nonalcoholic steatohepatitis (NASH)
 Mild elevations of the serum aminotransferases, less than fourfold elevated
ratio of AST to ALT is usually less than one.
Risk factors :
obesity
type 2 diabetes mellitus
hypertriglyceridemia

30. NASH initial evaluation : Ultrasonography
computed tomography (CT)
magnetic resonance imaging (MRI)
Ultrasonography
low sensitivity .less expensive.
in a patient in whom there is a high pretest probability of steatosis and tests for hepatitis B, C, and hemochromatosis are unremarkable, the least expensive test to look for steatosis is ultrasonography.

31. For differentiation between steatosis and NASH requires a liver biopsy.
Biopsy indications:
Peripheral stigmata of chronic liver disease
Splenomegaly
Cytopenia
Abnormal iron studies
Diabetes mellitus and/or significant obesity in an individual over the age of 45

32. Step two Non-hepatic causes of elevated aminotransferases
muscle disorders
thyroid disease
celiac disease
adrenal insufficiency
Anorexia nervosa

33. Muscle disorders Immediately after muscle injury,
 AST/ALT ratio is generally greater than three but approaches one within a few days because of a faster decline in the serum AST.
Peak AST and ALT levels are variable.
AST levels range ,000
ALT ratios range

34. Conditions that can cause muscle injury include
subclinical inborn errors of muscle metabolism,
acquired muscle disorders (such as polymyositis),
seizures
heavy exercise (such as long distance running).
muscle source :
creatine kinase
lactate dehydrogenase (LDH)
aldolase

35. Thyroid disorders
Thyroid disorders(hypothyroidism and hyperthyroidism ) can produce elevated aminotransferases by unclear mechanisms

36. Celiac disease
 Several reports have described elevated serum aminotransferases in patients with undiagnosed celiac disease
The cause is uncertain.
ALT usually slightly greater than AST

37. Adrenal insufficiency
 Aminotransferase elevation (1.5 to 3 times the upper limit of normal) has been described in patients with adrenal insufficiency (due to Addison's disease or secondary causes), including those without obvious clinical features of the disorder .
Aminotransferase levels normalize within one week following appropriate treatment.

38. Anorexia nervosa
 Anorexia nervosa has been associated with aminotransferase elevation by mechanisms that are not well understood.
In a series of 214 women, 12 percent had aminotransferase elevation.

39. Step three
  The next set of tests is aimed at identifying less common liver conditions:
Autoimmune hepatitis
Wilson disease
Alpha-1 antitrypsin deficiency

40. Autoimmune hepatitis young to middle-aged women screening test :
serum protein electrophoresis (SPEP).
More than 80 percent of patients with autoimmune hepatitis have hypergammaglobulinemia
Additional tests :
antinuclear antibodies (ANA)
smooth muscle antibodies (SMA)
liver-kidney type 1 microsomal antibodies (LKMA).

41. Wilson disease A genetic disorder of biliary copper excretion
diagnosis should be considered in patients up to the age of 40 years
screening test serum:
ceruloplasmin level,
reduced in approximately 85 percent of patients
Kayser-Fleischer rings
Dx:
liver biopsy for quantitative copper.

42. Alpha-1 antitrypsin deficiency
 Alpha-1 antitrypsin deficiency is an uncommon cause of chronic liver disease in adults. Decreased levels of alpha-1 antitrypsin in serum can be detected either by direct measurement of serum concentrations or by the absence of the alpha-1 peak on a serum protein electrophoresis.

43. Step four
 A liver biopsy is often considered in patients in whom all of the above testing has been unrevealing. However, in some settings, the best course may be expectant observation.

44. Whom to observe
only in patients in whom the ALT and AST levels are less than twofold elevated and no chronic liver condition has been identified by the above noninvasive testing.

45. Whom to biopsy
patients in whom the ALT and AST are persistently greater than twofold elevated.

46. Alkaline phosphatase Isoenzymes of ALP:
Liver
Bone
Placenta
Small intestine.
Patients over age 60 (1–11/2 times normal)
Children and adolescents undergoing rapid bone growth
Normal pregnancies due to the influx of placental alkaline phosphatase

47. Determining the source of the alkaline phosphatase
electrophoretic separation
GGT level or serum 5'-nucleotidase level
An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should prompt an evaluation for bone diseases.

48. Isolated alkaline phosphatase elevation
 Chronic cholestatic diseases
primary biliary cirrhosis (PBC)
primary sclerosing cholangitis
adult bile ductopenia
drugs such as androgenic steroids and phenytoin
infiltrative liver diseases
sarcoidosis
amyloidosis
Metastatic cancer to the liver

49. Isolated alkaline phosphatase elevation
Other cause:
Hodgkin's disease
Diabetes
Hyperthyroidism
Congestive heart failure
Inflammatory bowel disease

50. biliary dilatation suggests obstruction of the biliary tree.
Initial testing :
right upper quadrant ultrasonography
antimitochondrial antibodies (AMA), which are highly suggestive of PBC
biliary dilatation suggests obstruction of the biliary tree.
biliary dilatation or choledocholithiasis : MRCP or ERCP
positive AMA : liver biopsy

51. Patients in whom initial testing is unrevealing
If AMA and ultrasonography are both negative and the serum alkaline phosphatase is persistently more than 50 percent above normal for more than six months.
liver biopsy and either an ERCP or MRCP
If the alkaline phosphatase is less than 50 percent above normal, all of the other liver biochemical tests are normal, and the patient is asymptomatic:
observation

52. Gamma glutamyl transpeptidase
 GGT is found in hepatocytes and biliary epithelial cells.
Elevated levels of serum GGT
pancreatic disease
myocardial infarction
renal failure
chronic obstructive pulmonary disease
diabetes mellitus
alcoholism
medications such as phenytoin and barbiturates

53. GGT used to identify patients with occult alcohol use
sensitivity :52 to 94 percent.
GGT usage:
confirm the liver origin of an elevated ALP
support a suspicion of alcohol abuse in a patient with an elevated AST and an AST:ALT ratio of greater than 2:1)

56. Predominantly hepatocellular pattern with jaundice
 Common hepatocellular diseases that can cause jaundice :
Alcoholic hepatitis
viral hepatitis
toxic hepatitis (including drugs, herbal therapies)
end-stage cirrhosis from any cause
Wilson disease should be considered in young adults
Autoimmune hepatitis

57. Alcoholic hepatitis
Patients with alcoholic hepatitis typically have an AST:ALT ratio of at least 2:1.
The AST rarely exceeds 300 unit/L.
 DDX:
viral hepatitis and toxin-related injury severe enough to produce jaundice typically have aminotransferase levels greater than 500 unit/L, with the ALT greater than or equal to the AST.

58. Viral hepatitis 
 Patients with acute viral hepatitis can develop jaundice.
Diagnostic tests:
IgM antibody to hepatitis A virus
HBsAg
IgM anti-HBc
HCV AB and Hepatitis C viral RNA

59. Acute hepatitis C Dx: usually asymptomatic
uncommon cause of acute viral hepatitis that is clinically evident.
Dx:
HCV AB and Hepatitis C viral RNA

60. Toxic hepatitis Predictable drug reactions are dose-dependent
The classic example is acetaminophen hepatotoxicity.
Unpredictable, or idiosyncratic, drug reactions are not dose dependent Virtually any drug can cause an idiosyncratic reaction.

61. Environmental toxins industrial chemicals such as vinyl chloride
herbal preparations containing pyrrolizidine alkaloids (Jamaica bush tea)
mushrooms Amanita phalloides.

62. Shock liver (ischemic hepatitis)
Cause: prolonged period of systemic hypotension
following a cardiac arrest
severe heart failure
Lab tests:
serum aminotransferase levels (exceeding 1000  or 50 times the upper limit of normal)
lactic dehydrogenase
Hepatic function usually returns to normal within several days of the acute episode.

63. Wilson disease present with acute and even fulminant hepatitis. Dx:
patients younger than 40
concomitant hemolytic anemia

64. Autoimmune hepatitis
 Patients with autoimmune hepatitis can present with acute and even fulminant hepatitis.
Dx:
clinical setting
exclusion of other causes
serologic testing
liver biopsy

65. Predominantly cholestatic pattern
First step :
cholestasis is due to an intra- or extrahepatic cause
Right upper quadrant ultrasonography
NO biliary dilatation intrahepatic cholestasis
Biliary dilatation extrahepatic cholestasis

66. ultrasonography False negative results:
partial obstruction of the bile duct
cirrhosis
primary sclerosing cholangitis where scarring prevents the intrahepatic ducts from dilating

67. Extrahepatic cholestasis
Choledocholithiasis is the most common cause of extrahepatic cholestasis.
elevation of the serum alkaline phosphatase out of proportion to the aminotransferases
elevation of aminotransferases to greater than 1000 int. unit/L may be seen early in the course

68. MRCP:
noninvasive technique for imaging the bile and pancreatic ducts
ERCP:
gold standard for identifying choledocholithiasis
Unsuccessful ERCP
transhepatic cholangiography
Choledocholithiasis can also be detected with endoscopic ultrasonography(EUS)

69. Malignant causes of extrahepatic cholestasis :
pancreatic
gallbladder
ampullary
Cholangiocarcinoma
Hilar lymphadenopathy due to metastases from other cancers (eg, breast, colon) may cause obstruction of the extrahepatic biliary tree.

70. PSC :strictures limited to the extrahepatic biliary tree.
Chronic pancreatitis uncommonly causes strictures of the distal common bile duct

71. AIDS cholangiopathy Cause: cholangiographic appearance: Lab tests:
infection of the bile duct epithelium with cytomegalovirus [CMV] or Cryptosporidium
cholangiographic appearance:
similar to that of PSC
Lab tests:
elevated serum alkaline phosphatase levels (around 800 int. unit/L) 
normal or near normal bilirubin level.

72. Intrahepatic cholestasis
Viral hepatitis: Hepatitis A, EBV, CMV
Alcoholic hepatitis
Drug toxicity
Pure cholestasis : anabolic and contraceptive steroids
Mixed cholestasis/hepatitis : chlorpromazine, erythromycin estolate
Chronic cholestasis : chlorpromazine and prochlorperazine
Primary biliary cirrhosis
Primary sclerosing cholangitis
Vanishing bile duct syndrome
Chronic rejection of liver transplants
Sarcoidosis
Drugs

73. Intrahepatic cholestasis
Inherited
Benign recurrent cholestasis
Progressive intrahepatic familial cholestasis
Gilbert's syndrome
Crigler-Najjar syndrome types 1 and 2
Dubin-Johnson syndrome
Rotor syndrome
Alagille syndrome
Cholestasis of pregnancy
Total parenteral nutrition
Non-hepatobiliary sepsis
Benign postoperative cholestasis
Paraneoplastic syndrome (Stauffer's syndrome)

74. Drug-induced cholestasis
Usually Reversible after elimination of the offending drug
Cholestasis :
Most common:anabolic and contraceptive steroids.
Other drugs: chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, erythromycin estolate, trimethoprim-sulfamethoxazole, and penicillin-based antibiotics such as ampicillin and dicloxacillin.
chronic and associated with progressive fibrosis:
chlorpromazine and prochlorperazine. 

75. Primary biliary cirrhosis
middle-aged women
progressive destruction of interlobular bile ducts
Dx:
antimitochondrial antibodies(AMA), which are found in 95 percent of patients. 

76. Primary sclerosing cholangitis
destruction and fibrosis of larger bile ducts.
The disease may involve only the intrahepatic ducts and present as intrahepatic cholestasis.
65 % of patients, both intra- and extrahepatic ducts are involved.
Dx:
MRCP or ERCP
multiple strictures of bile ducts with dilatations proximal to the strictures.
A majority of patients with PSC have inflammatory bowel disease(IBD).

77. Vanishing bile duct syndrome
ductopenia
rare
Causes:
chronic graft rejection after liver transplantation
sarcoidosis
drugs : chlorpromazine
Idiopathic

78. Cholestasis of pregnancy
second and third trimesters
Resolves after delivery

79. Other causes of intrahepatic cholestasis
total parenteral nutrition 
non-hepatobiliary sepsis
benign post-operative cholestasis
paraneoplastic syndrome (Stauffer's syndrome):
renal cell carcinoma
Hodgkin lymphoma
medullary thyroid cancer
renal sarcoma
T-cell lymphoma
prostate cancer
several gastrointestinal malignancies

80. خسته نباشید