Liver function tests: Hepatic

1
Liver function testsHepatic

• Megan Chan, PGY-1
• UHCMC 2015

2
Liver function

• Bile synthesis secretion
• Bilirubin production and excretion
• Detoxification e.g. converts ammonia into urea
• First pass metabolism
• Phase 1 reaction via cytochrome P450 enzymes
• Phase 2 reactionconjugation of substances
• Kupffer cellsliver macrophages

• Metabolic function
• Gluconeogenesis, glycogen storage
• Synthesis of plasma proteins, albumin, clotting
  factors, non-essential amino acids
• Fatty acid oxidation, synthesis of cholesterol,
  lipoproteins

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Liver anatomy

• Afferent vessels
• Hepatic artery30 of blood flow, oxygenated
• Portal vein70 of blood flow
• Efferent vessels
• Bile duct
• Central vein (aka Terminal hepatic vein)
• Portal Triad
• Bile duct Hepatic artery Portal vein

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http//studydroid.com/imageCards/0a/k1/card-111431
24-back.jpg
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Bilirubin
First Aid for USMLE Step 1
6
Guess the LFTs
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Acute hepatitis

• AST
• Elevated
• ALT
• Elevated
• Alk Phos
• Normal
• T bili
• Normal

http//www.atsu.edu/faculty/chamberlain/Website/le
ctures/lecture/hepatit2.htm
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Cirrhosis

• AST
• Normal/Elevated
• ALT
• Normal/Elevated
• Alk Phos
• Normal/Elevated
• T bili
• Normal/Elevated

http//hepatitiscnewdrugresearch.com/evaluation-st
aging-and-monitoring-of-chronic-hepatitis-c.html
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Cirrhosis

• As cirrhosis progresses, Total Bili increases
  because the liver can still conjugate bilirubin
  but cant excrete it.

• MELD Score for 3 month mortality
• Total bilirubin
• Serum creatinine
• INR
• Dialysis

40 --71.3 mortality 30-39 52.6
mortality 20-29 19.6 mortality 10-19 6.0
mortality lt9 1.9 mortality
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Child pugh score

• Classification to assess severity of liver
  disease hepatic functional reserve

Points 1 2 3
Ascites None Controlled Uncontrolled
Bilirubin lt2.0 2.0-3.0 gt3.0
Encephalopathy None Minimal Severe
INR lt1.7 1.7-2.2 gt2.2
Albumin gt3.5 2.8-3.5 lt32.8
Classification A B C
Total points 5-6 7-9 10-15
1-yr survival 100 81 45
2-yr survival 85 57 35
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Liver transplant

• Evaluate when Child Class B or MELD 10
• Indications
• Recurrent/severe encephalopathy
• Refractory ascites
• SBP
• Recurrent variceal bleeding
• Hepatorenal or Hepatopulmonary syndrome
• HCC if no single lesion gt 5cm or 3 lesions w/
  largest 3 cm
• Fulminant hepatic failure
• Contraindications
• Advanced HIV, active substance abuse (ETOH w/in 6
  mo), sepsis, extrahepatic malignancy, severe
  comorbidity (esp cardiopulm), persistent
  non-compliance

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Practice cases
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Case 1

• 65 y/o male with 25 year history of alcohol and
  tobacco abuse who presents with abdominal
  swelling and confusion. Pt reports an
  unintentional 15 lbs weight gain and frequent
  forgetfulness. On exam, pt is AO x1 (only to
  person), is slow to answer questions and often
  answers inappropriately. Pt has scleral icterus,
  distended abdomen with fluid wave, and several
  ecchymoses on his lower extremities. Slight
  asterixis is observed.
• What is the most likely diagnosis?

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Case 1

• 65 y/o male with 25 year history of alcohol and
  tobacco abuse who presents with abdominal
  swelling and confusion. Pt reports an
  unintentional 15 lbs weight gain and frequent
  forgetfulness. On exam, pt is AO x1 (only to
  person), is slow to answer questions and often
  answers inappropriately. Pt has scleral icterus,
  distended abdomen with fluid wave, and several
  ecchymoses on his lower extremities. Slight
  asterixis is observed.
• What is the most likely diagnosis?
• Alcoholic Cirrhosis

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Early/Late Cirrhosis
http//radiopaedia.org/cases/cirrhosis
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Histology

• Focal hepatocellular necrosis with 3
  characteristics
• Fibrosis
• Nodular regeneration
• Distortion of hepatic architecture

http//tissupath.com.au/education-medical-student-
liver/
http//medchrome.com/basic-science/pathology/morph
ology-alcoholic-liver-disease/
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liver stamp

• Liver US with dopplers (for portal vein
  thrombosis)
• ANA, Anti smooth muscle Ab (autoimmune)
• Anti-mitochondrial Ab (primary biliary cirrhosis)
• Ceruloplasmin (Wilsons)
• Ferritin Iron studies w/ TIBC (Hemochromatosis)
• HepBs Ag, HepBs Ab, HepBc Ab
• HepC Ab, HepC PCR
• Alpha-antitrypsin

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liver stamp
Average cost?
1,200
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cirrhosis Etiology

• Fatty liver diseases
• Alcoholic liver disease
• NASH/NAFLD
• Viral hepatitis Hep B, C, D
• Autoimmune
• Autoimune hepatitis
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Cardiovascular
• Budd-Chiari syndrome
• Chronic right heart failure

• Chronic biliary disease
• Recurrent bacterial cholangitis
• Bile duct stenosis
• Storage diseases
• Hemochromatosis
• Wilson disease
• a-1-antitrypsin deficiency
• Meds APAP toxicity, MTX
• Cryptogenic 10-15

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Diagnostic imaging

• Ultrasound
• Surface nodularity 88 sensitive, 82-95
  specific (1)
• Coarse heterogeneous echotexture
• Signs of portal HTN
• Portal vein gt13mm 42 sensitive, 95-100
  specific (2)
• Splenomegaly, ascites
• CT insensitive in early cirrhosis
• MRI also insensitive in early cirrhosis, but
  significant role in assessing small
  hepatocellular carcinoma (HCC)develops in 10-25
• Liver biopsy gold standard for diagnosis

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Treatment

• Ascites
• Furosemide Spironolactone with goal negative
  1L/day (80 effective)
• Lasix Aldactone ratio of 25 helps maintain K
  (thus Lasix 40mg qday, Aldactone 100mg qday
  initially)
• Low-sodium diet (1-2 g/day)
• Refractory Ascites no response on max doses of
  Lasix (160mg) Aldactone (400mg)
• LVP 4-6L (does not improve mortality)
• Albumin replacement controversial. AASLD 2009
  guidelines recommend if gt5L removed, provide 6-8
  g/L of albumin 25 (IIA, Grade C)
• If gt5L removed, can have post-paracentesis
  circulatory dysfxn via RAAS activation
• TIPS (? ascites in 75, improves mortality but ?
  HE, 40 need revision for stent stenosis)
• Hepatic encephalopathy
• Lactulose
• Hepatorenal syndrome
• Transplantation

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Case 2

• 57 y/o known HepC cirrhotic presents with
  malaise, fevers and chills. Her husband reports
  she has been intermittently confused over the
  past few days despite taking her lactulose. Exam
  shows significant ascites and diffuse abdominal
  tenderness to palpation. Diagnostic paracentesis
  reveals straw-colored fluid with pH lt 7.3, WBC
  1000 with 70 PMNs, glucose 35, total protein 30.
  SAAG is calculated to be 1.5.
• What is the most likely diagnosis?

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Case 2

• 57 y/o known HepC cirrhotic presents with
  malaise, fevers and chills. Her husband reports
  she has been intermittently confused over the
  past few days despite taking her lactulose. Exam
  shows significant ascites and diffuse abdominal
  tenderness to palpation. Diagnostic paracentesis
  reveals straw-colored fluid with pH lt 7.3, WBC
  1000 with 70 PMNs, glucose 35, total protein 30.
  SAAG is calculated to be 1.5.
• What is the most likely diagnosis?
• Spontaneous Bacterial Peritonitis (SBP)

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Sbp

• Develops in 20 cirrhotics, 10-25
  asymptomatic, 20 mortality
• Risk factors
• AFTP lt 1 g/dL, current GIB, hx of SBP,
  Lines/catheters, Childs C cirrhosis, fulminant
  hepatic failure
• Culture can be negative in 30-50, Gram stain
  in only 5-10
• 70 is GNR (E.coli, Klebs), 30 GPC (S. pneumo,
  Enterococcus)

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SBP

• Treatment
• Cefotaxime 2gm IV q8hrs x 5 days, Norfloxacin PO
  in uncomplicated SBP
• IV albumin 1.5g/kg at time of dx then 1g/kg on
  day 3 (? survival and ? renal impairment)
• If no improvement, repeat para at 48 hrs (25 ?
  PMN count tx success)
• Prophylaxis
• GI bleeds Norfloxacin 400mg PO q12 hrs
• Hx of SBP Norfloxacin400mg qd, Cipro 750mg qwk,
  Bactrim DS qd (? 1 yr recurrence from 70 to 20,
  ? survival)

http//medicine.ucsf.edu/education/resed/Chiefs_co
ver_sheets/SBP,20cirrhosis,20empyema.pdf
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ASCITES Pathophysiology

• Also
• 1. Hypoalbuminemia ? ? serum oncotic pressure
• 2. ? hepatic lymph ? ? splanchnic pressure

http//medical-dictionary.thefreedictionary.com/as
cites
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PARACENTESIS

• What tests would you send?
• 4 Cs Cells, Culture, Chemistry, Cytology
• Cell count and differential, gram stain, culture,
  albumin, total protein, glucose, LDH, cytology
• Optional amylase, bilirubin, Cr, TG, AFB cx
  adenosine deaminase
• How do you calculate the SAAG?
• SAAG Serum albumin Ascites albumin
• What does the SAAG indicate?
• If 1.1 g/dL, portal HTN is very likely (97
  accurate1)
• If lt 1.1 g/dL, portal HTN is unlikely.

Runyon et al. The serum-ascites albumin gradient
is superior to the exudates-transudate concept in
the differential diagnosis of ascites. Annals of
Internal Medicine 1992 117215-20.
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Paracentesis

• SAAG 1.1

• SAAG lt 1.1

• Peritonitis TB, ruptured viscus
• Peritoneal carcinomatosis
• Pancreatitis
• Vasculitis
• Hypoalbuminemia (e.g. nephrotic syndrome)
• Meigs syndrome (ovarian tumor)
• Bowel obstruction/infarction
• Post-op lymphatic leak

• Sinusoidal
• Cirrhosis(81), SBP
• Acute hepatisis
• Extensive malignancy (HCC/mets, 10)
• Postsinusoidal
• R heart failure (3)
• Budd-Chiari Syndrome
• Presinusoidal
• Portal/splenic vein thrombosis

Runyon et al. The serum-ascites albumin gradient
is superior to the exudates-transudate concept in
the differential diagnosis of ascites. Annals of
Internal Medicine 1992 117215-20.
29
Paracentesis

• Ascites fluid total protein (AFTP) useful when
  SAAG 1.1
• Cirrhosis (AFTP lt 2.5) vs Cardiac ascites (AFTP gt
  2.5)
• Bloody fluid 50 with HCC, 22 with malignancy
• For traumatic taps, subtract 1 PMN for every 250
  RBC.
• Cell count PMN 250 cells/µL SBP (93
  sensitivity, 94 specificity)
• Total protein lt 1 g/dL ? high risk for SBP
• Glucose ? in infection and malignancy
• LDH ? in infection and malignancy
• Amylase (fluid/serum ratio gt 0.4) pancreatitis,
  gut perforation
• TG gt 1000 in chylous ascites
• Cytology overall sensitivity 58-75
• However 100 sensitive in peritoneal
  carcinomatosis (2/3 of malignant-related ascites)

Runyon et al. The serum-ascites albumin gradient
is superior to the exudates-transudate concept in
the differential diagnosis of ascites. Annals of
Internal Medicine 1992 117215-20.
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Bacterial Peritonitis
Type Ascites Cell Count Ascites Culture
Sterile lt 250 PMNs Neg
Spontaneous bacterial peritonitis (SBP) 250 PMNs (1 organism)
Culture neg neutrocytic ascites (CNNA) 250 PMNs Neg
Nonneutrocytic bacterascites (NNBA) lt 250 PMNs (1 organism)
Secondary 250 PMNs (polymicrobial)
Peritoneal dialysis-associated 100, PMNs predom
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Case 3

• 35 y/o male presents with fatigue and tea-colored
  urine for 5 days. Exam reveals jaundice and
  tender heaptomegaly but is otherwise
  unremarkable. Labs are significant for AST 2400,
  ALT 2640, Alk Phos 210, and Total Bilirubin 8.6.
• Which of the following is least likely to cause
  this clinical picture?
• Acute hepatitis A infection
• Acute hepatitis B infection
• Acute hepatitis C infection
• Acetaminophen ingestion
• Budd-Chiari Syndrome

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Case 3

• Which of the following is least likely to cause
  this clinical picture?
• Acute hepatitis A infection
• Acute hepatitis B infection
• Acute hepatitis C infection
• Acetaminophen ingestion
• Budd-Chiari Syndrome
• Extreme elevations in transaminases usually fall
  into 3 major categories viral infections, toxic
  ingestions, and vascular/hemodynamic causes
  (shock liver). Hep C does not typically cause
  acute infection.

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Case 4

• 24 y/o patient is admitted to the MICU with
  obtundation and jaundice over 1-2 days. No
  further history is available. The following labs
  are obtained
• Total Bili 7.2, Direct Bili 4.0, AST 1478, ALT
  1056, Alk Phos 132, INR 3.1, Albumin 3.6.
• All of the following tests are indicated except?
• Antinuclear Ab (ANA)
• Ceruloplasmin
• Hepatitis B surface Ag
• ERCP
• Toxicology screen

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Case 4

• All of the following tests are indicated except?
• Antinuclear Ab (ANA)
• Ceruloplasmin
• Hepatitis B surface Ag
• ERCP
• Toxicology screen
• When evaluating a patient with jaundice, initial
  steps include determining whether the
  hyperbilirubinemia is predominantly unconjugated
  or conjugated and whether there is any other
  evidence for hepatobiliary dysfxn. Next is to
  discriminate into a predominantly cholestatic or
  hepatocellular pattern. In this case, the pt has
  a hepatocellular pattern with AST/ALT elevated
  out of proportion to Alk Phos.

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Harrisons Internal Medicine
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Case 5

• 41 y/o male who presents to your clinic with a
  week of jaundice. He notes pruritus, icterus,
  and dark urine. He denies fever or abdominal
  pain. Exam is unremarkable except for jaundice.
• Labs Total bili 6.0 , direct bili 5.1, AST 84 ,
  ALT 92, Alk phos 662.
• CT scan of abdomen is unremarkable. RUQ
  ultrasound shows a normal bile duct but does not
  visualize the common bile duct.
• What is the most appropriate next management
  step?
• Antibiotics and observation
• ERCP
• Hepatic serologies
• HIDA scan
• Serologies for antimitochondrial Ab

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Case 5

• What is the most appropriate next management
  step?
• Antibiotics and observation
• ERCP
• Hepatic serologies
• HIDA scan
• Serologies for antimitochondrial Ab
• Anatomic abnormalities are more common when there
  is a cholestatic pattern of injury (Alk Phos
  elevated out of proportion to AST/ALT). Painless
  jaundice always requires extensive workup with
  concern for malignant causes (e.g.
  cholangiocarcinoma, tumor of ampulla of vater) vs
  nonmalignant causes (e.g. primary sclerosing
  cholangitis), which may only be detected by
  direct visualization with ERCP. Negative CT does
  not rule out source of cholestatis in biliary
  tree. Furthermore, ERCP is useful therapeutically
  with stenting to alleviate the obstruction.

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Harrisons Internal Medicine
39
Case 6

• 61 y/o male is admitted to your service for new
  onset ascites. You perform a paracentesis with
  the following results of the non-bloody
  peritoneal fluid
• WBC 300 with 35 PMNs, albumin 1.2, protein 2.6,
  TG 320
• Peritoneal cultures are pending. Serum albumin
  2.7.
• Which of the following is the most likely
  diagnosis?
• Peritoneal tuberculosis
• Peritoneal carcinomatosis
• Congestive heart failure
• Bacterial peritonitis
• Chylous ascites

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Case 6

• Which of the following is the most likely
  diagnosis?
• Peritoneal tuberculosis
• Peritoneal carcinomatosis
• Congestive heart failure
• Bacterial peritonitis
• Chylous ascites
• SAAG 1.5, AFTP 2.6 ? Cardiac ascites
• Low WBC and PMNs make SBP and TB less likely

41
Case 7

• An alcoholic cirrhosis patient has increasing
  ascites despite dietary sodium control and
  diuretics. A paracentesis shows clear, turbid
  fluid. There are 2300 WBCs and 150 RBC.
  Differential shows 75 lymphocytes. Fluid
  protein is 3.2 and SAAG is 1.0.
• What is the most appropriate next test?
• Adenosine deaminase activity of ascitic fluid
• CT scan of liver
• Peritoneal biopsy
• None consider transplant evaluation

42
Case 7

• What is the most appropriate next test?
• Adenosine deaminase activity of ascitic fluid
• CT scan of liver
• Peritoneal biopsy
• None consider transplant evaluation
• In pts with chronic cirrhosis who develop new or
  worsening ascites without dietary or medication
  nonadherence, consider an occult disorder (e.g.
  peritoneal TB, HCC, portal vein thrombosis). ?
  WBC is more common in neoplasm, bacterial
  peritonitis, or TB. Predominance of lymphocytes
  raises the suspicion for TB. SAAG is classically
  low in TB peritonitis but can be elevated in
  concomitant cirrhosis/transudative ascites. The
  sensitivity of ADA is poor in those with
  cirrhosis 2/2 poor T cell-mediated response. Thus
  peritoneal biopsy or visual diagnosis during
  laparoscopy is likely needed to confirm the
  diagnosis.

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Paracentesis

• SAAG 1.1

• SAAG lt 1.1

• Peritonitis TB, ruptured viscus
• Peritoneal carcinomatosis
• Pancreatitis
• Vasculitis
• Hypoalbuminemia (e.g. nephrotic syndrome)
• Meigs syndrome (ovarian tumor)
• Bowel obstruction/infarction
• Post-op lymphatic leak

• Sinusoidal
• Cirrhosis(81), SBP
• Acute hepatisis
• Extensive malignancy (HCC/mets, 10)
• Postsinusoidal
• R heart failure (3)
• Budd-Chiari Syndrome
• Presinusoidal
• Portal/splenic vein thrombosis

Runyon et al. The serum-ascites albumin gradient
is superior to the exudates-transudate concept in
the differential diagnosis of ascites. Annals of
Internal Medicine 1992 117215-20.
44
When to Tap/REtap

• New ascites
• Admission of all patients with cirrhotic ascites
• Deterioration in clinical status
• Complication of cirrhosis (GI bleed, confusion)
• Polymicrobial culture or culture with PMN lt 250
  (MNB that may be early SBP)
• Retap 24-48 hrs after treatment started in pts
  with PMNgt 1000 (associated with 88 mortality) or
  lack of improvement.

http//medicine.ucsf.edu/education/resed/Chiefs_co
ver_sheets/SBP,20cirrhosis,20empyema.pdf
45
Case 8

• When evaluating a patient with chronic ascites, a
  SAAG gt 1.1 is consistent with all of the
  following diagnoses except?
• Cirrhosis
• Congestive heart failure
• Constrictive pericarditis
• Hepatic vein thrombosis
• Nephrosis

46
Case 8

• When evaluating a patient with chronic ascites, a
  SAAG gt 1.1 is consistent with all of the
  following diagnoses except?
• Cirrhosis
• Congestive heart failure
• Constrictive pericarditis
• Hepatic vein thrombosis
• Nephrosis

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Paracentesis

• SAAG 1.1

• SAAG lt 1.1

• Peritonitis TB, ruptured viscus
• Peritoneal carcinomatosis
• Pancreatitis
• Vasculitis
• Hypoalbuminemia (e.g. nephrotic syndrome)
• Meigs syndrome (ovarian tumor)
• Bowel obstruction/infarction
• Post-op lymphatic leak

• Sinusoidal
• Cirrhosis(81), SBP
• Acute hepatisis
• Extensive malignancy (HCC/mets, 10)
• Postsinusoidal
• R heart failure (3)
• Budd-Chiari Syndrome
• Presinusoidal
• Portal/splenic vein thrombosis

Runyon et al. The serum-ascites albumin gradient
is superior to the exudates-transudate concept in
the differential diagnosis of ascites. Annals of
Internal Medicine 1992 117215-20.
48
http//image.slidesharecdn.com/complicationsofcirr
hosis-100914093820-phpapp02/95/complications-of-ci
rrhosis-18-728.jpg?cb1284460955
49
Case 9

• 28 y/o woman who is 30 weeks pregnant presents
  with 2 week history of pruritus and scleral
  icterus. It is her first pregnancy, and she has
  no significant medical hx. She does not drink
  alcohol and takes only a prenatal vitamin.
  Vitals are stable. Exam reveals a gravid uterus,
  mild scleral icterus and linear excoriations on
  the skin. There is no ascites or lower extremity
  edema.

50
Case 9

• Labs reveal
• Hb 13.4 Platelet 275.000
• AST 44, ALT 38, Total Bili 4.2, Direct Bili 2.3,
  Alk Phos 180
• LDH 82, INR 1.0
• Hep Bs Ag Neg, Hep Bs Ab Positive,
• Hep C Ab Neg, Hep A Ab (IgG) Positive
• ANA negative, Anti-smooth muscle Ab neg
• Ultrasound of the liver is normal.

51
Case 9

• Which of the following is the most likely
  diagnosis?
• Acute fatty liver of pregnancy
• Acute hepatitis A infection
• Cholestasis of pregnancy
• HELLP syndrome

52
Case 9

• Which of the following is the most likely
  diagnosis?
• Acute fatty liver of pregnancy
• Acute hepatitis A infection
• Cholestasis of pregnancy
• HELLP syndrome
• Cholestasis of pregnancy is the most common
  pregnancy-related liver disorder that is benign
  for the mother but increases risk for pre-term
  delivery and fetal loss if untreated. It often
  presents in the 2nd or 3rd trimester of pregnancy
  and treatment is with ursodeoxycholic acid for
  symptomatic treatment.
• In contrast acute fatty liver occurs in the 3rd
  trimester and is associated with high AST/ALT,
  high bilirubin and fat on liver US.
• HELLP syndrome is part of spectrum of
  eclampsia/pre-eclampsia and presents with HTN,
  hemolytic anemia, proteinuria high AST/ALT,
  thrombocytopenia. It occurs during 3rd trimester
  and up to 48 hrs postpartum. Tx is delivery of
  the baby.

53
Case 10

• 45y/o male admitted for 2 day hx of fever and
  abdominal pain. Medical hx is notable for HepC
  cirrhosis and esophageal varices. Medications
  include furosemide, spironolactone, nadolol, and
  lactulose. Pt is afebrile, BP 100/50, HR 84.
  Abdominal exam is consistent with ascites and is
  nontender to palpation.
• Labs Hb 10, WBC 3500, Plt 70,000, INR 1.5,
  Albumin 2.5, Alk Phos 220, AST 40, ALT 30, T bili
  4, Cr 1.8, UA normal.
• Abdominal US shows cirrhosis, spenomegaly,
  ascites. Portal hepatic veins are patent.
  Diagnostic paracentesis shows WBC 2000 with 20
  PMNs, Total protein 1, Albumin 0.7.
• Which of the following is the most appropriate
  treatment?
• Cefotaxime
• Cefotaxime and albumin
• Furosemide and spironolactone
• LVP
• Observation

54
Case 10

• Which of the following is the most appropriate
  treatment?
• Cefotaxime
• Cefotaxime and albumin
• Furosemide and spironolactone
• LVP
• Observation
• In patients with SBP, the concomitant use of IV
  albumin with antibiotic therapy is associated
  with a survival benefit compared with antibiotic
  therapy alone.

55
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  McGraw Hill. New York, NY.
• http//medicine.ucsf.edu/education/resed/Chiefs_co
  ver_sheets/SBP,20cirrhosis,20empyema.pdf
• http//radiopaedia.org
• Special thanks to Dr. Caroline Soyka for the
  inspiration!