LFT Review
Transcript of LFT Review
LFT MODULEDepartment of MedicineChief Residents
Introduction
LFT abnormalities fall into several patterns which help to differentiate the underlying liver disease: hepatocellular damage (high
transaminases) cholestasis (high alkaline phosphatase) poor synthetic function
Note that elevated Bilirubin can occur in any of the above scenarios depending on severity or it can be isolated
Introduction
An appropriate response to abnormal LFTs requires an assessment of: Pattern (hepatocellular or cholestatic) Magnitude of elevation
Often expressed in multiples of the upper limit of normal (ULN)
Duration of abnormality Associated symptoms Clinical evidence of cirrhosis
Representation of LFTs
AST AΦ TB TP
ALT DB Alb
Normal Values
<35 30-120
<1.0
6-8
<35<0.4
4-6
Case #1
77 85 0.6 7.8
71 0.2 4.1
A 45 year-old male presents to your Bellevue clinic to establish care. He has notseen a doctor in over 10 years, but has been feeling well. He is unaware of any medical history. His exam is unremarkable. His labs are normal except for theLFTs below:
Case #1 Study Questions
Describe these LFTs What is dominant pattern of
abnormality? Classify the magnitude of each finding
What is the Differential Diagnosis? What is the appropriate next step in
workup (further history, exam maneuvers, lab/imaging)?
Case #1 Discussion
LFT analysis: This patient has an isolated mild transaminitis (2-3x ULN) ALT > AST
Differential Diagnosis of Mild Transaminitis Ingestion: Alcohol and Medications Infection: Hep B and C Immune: Autoimmune Hepatitis Inherited: Wilson’s Dz, Hemochromatosis BMI : Hepatic Steatosis
Case #1 Discussion
What is the workup of a mild transaminitis? Chart Review
Is this finding new or chronic? Think about repeating the test
History Alcohol history Risk factors for Hep B and Hep C Medication review, focusing on new meds Autoimmune history Family history of liver disease
Case #1 Discussion
What is the workup of a mild transaminitis? Physical Exam
Bronzed Skin Kayser-Fleischer Rings Track marks
Labs (remember the 5 I’s) Hep C Ab; Hep B Surface Ag & Ab, Core IgG and IgM Iron studies, ceruloplasmin level, alpha-1 antitrypsin
phenotype ANA, Anti-smooth muscle Ab, Anti-LKM Ultrasound is not unreasonable to rule out NAFLD
Question: Your patient is Hep BsAg +, BsAb -, HBV DNA negative…can this explain his transaminitis?
Case #2
1218 191 3.8 7.8
1055 1.6 3.6
A 20 year-old female was found down in her apartment when she did not show up to her first day of class after winter break. Her apartment has evidence of empty bottles of alcohol. No pill bottles were found. In the ER she was acutely jaundiced, unresponsive, but hemodynamically stable.
Case #2 Study Questions
Describe these LFTs What is dominant pattern of abnormality? Classify the magnitude of each finding
What is the Differential Diagnosis? Three lab tests that are absolutely crucial
were not yet given. What are they and how would they guide management?
Case #2: Discussion
LFT Analysis Predominant pattern: Severe
hepatocellular injury Mild cholestasis (AP < 2x ULN) Elevated bili due to hepatocellular injury Evidence of mild synthetic dysfunction
Case #2: Discussion
The Differential Diagnosis of AST & ALT >1000 is small….. Ischemic Hepatitis Acute Viral Hepatitis (Hep A, Hep E) Tylenol Toxicity
What are the three crucial tests? Tylenol Level Creatinine and INR (to calculate MELD
Score)
Case #2: Discussion
Why is Tylenol level needed NOW? To guide the emergent use of N-Acetyl-Cystine To make a diagnosis
Why is creatinine and INR needed NOW? With Bili and Albumin, it is used to calculate a
MELD score in fulminant hepatic failure (0.957 * ln(Serum Cr) + 0.378 * ln(Serum
Bilirubin) + 1.120 * ln(INR) + 0.643 ) * 10 The MELD score will define 90-day mortality
and stratify need for liver transplant evaluation
Case #2 Discussion
Case #3
221 135 4.1 6.2
103 2.2 3.2
A homeless 63 year-old male with ETOH cirrhosis is brought in by NYPD for disorderly conduct. He endorses diffuse abdominal pain. He is afebrile and tremulous. His WBC count is elevated. His ETOH level is 0.
Case #3 Study Questions
Describe these LFTs What is dominant pattern of abnormality? Classify the magnitude of each finding
What is the Differential Diagnosis? What clinical information is needed to judge
the severity of his cirrhosis? An order for steroids is written in the ER. Do
you agree with it? What info is needed to decide if it is appropriate?
Case #3 Discussion
LFT Analysis Moderate transaminitis with AST/ALT >2 Mild elevation in Alk Phos Diminished synthetic function (Albumin
<3.2) Mixed hyerbilirubinemia
Likely multifactorial In proportion to the above derangements
Dominant pattern: Acute transaminitis with chronic synthetic dysfunction
What is the mechanism for this phenomenon? Answer to follow
Case #3 Discussion
Differential Diagnosis ETOH cirrhosis can explain the synthetic
dysfunction The moderate transaminitis carries a broad
differential, but Alcoholic Hepatitis must be #1 Why? Classic AST/ALT >2 withAST <8x ULN ALT production depends on pyridoxal 5-
phosphate, which is diminished in alcoholics Danger to patient if unrecognized
Case #3 Discussion
An order for steroids is written in the ER. Do you agree with it? What info is needed to decide if it is appropriate? Prednisolone is indicated in severe cases of
alcoholic hepatitis Severe cases are defined by a Maddrey
Discriminant Function score >32 4.6 * (Pt's PT - Control PT) + TBili In some institutions, pentoxyphylline is
substituted for prednisolone
Case #3 Discussion
What clinical information is needed to judge the severity of his cirrhosis?
Child-Pugh ClassQuestion: In what situations is it importantto know a patient’s Child-Pugh class?
Transaminitis Summary
Transaminitis Summary
Consider non-hepatic causes of transaminitis: Celiac Disease (may be occult) Thyroid Disease Adrenal Insufficiency Myocardial Infarction
AST was “the troponin” of the 1950’s and 60’s Muscle disorders or inborn metabolism
defects Strenuous exercise
Case #4
25 213 1.1 8.2
18 0.3 3.8
You are medical consult asked to evaluate a G1P0 female at 28 3/7 weeks for A mild pruritic maculopapular rash on the extremities and for the abnormal LFTs below. You learn that these LFTs are new from 1 year ago, but similar to those from her last outpatient appointment 2 weeks ago.
Case #4 Study Questions
Describe these LFTs What is dominant pattern of abnormality? Classify the magnitude of each finding
What is the differential diagnosis? What test would be ordered next and why? What other clinical scenarios might give
this same pattern and magnitude of LFT?
Case #4 Discussion
LFT Analysis Normal Transaminases Moderately elevated Alk Phos (>50% ULN) Synthetic function grossly intact Borderline elevation in bilirubin Predominant Pattern: Moderate cholestasis
without elevated bilirubin
What test should be ordered next? GGT
Case #4 Discussion
Case #4 Discussion
Let’s say that her GGT was high… the dfdx is extrahepatic vs. intrahepatic cholestasis
Case #4 Discussion
In a pregnant patient with mild cholestasis, consider cholestasis of pregnancy, which may present as a pruritic rash as in this case
If GGT is negative, consider physiological rise in alk phos from the placenta (up to 50% increase from ULN)
Although not part of this case, always consider the HELLP syndrome in a pregnant patient with transaminitis. It is the DIC of pregnancy
Case #4 Discussion
Intrahepatic cholestasis
Viral hepatitis
Alcoholic hepatitis
Nonalcoholic steatohepatitis
Primary biliary cirrhosis
Drugs and toxins - eg, alkylated steroids, chlorpromazine, herbal medications (eg, Jamaican bush tea), arsenic
Sepsis and hypoperfusion states
Infiltrative diseases - eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis
Total parenteral nutrition
Postoperative patient
Following organ transplantation
Hepatic crisis in sickle cell disease
Pregnancy
End-stage liver disease
• The history and pattern suggests a subtle intrahepatic cholestasis
•The differential can be long…including atypical presentation of hepatocellular injury
•Common Scenarios we might see•Sepsis•Steroid Use•TPN•CHF•Hepatic Infiltration
Case #5
21 115 3.9 7.5
24 0.4 4.1
A 21 year-old man presents with recurrent episode of sinusitis. He is otherwise healthy; you prescribe amoxicillin. He returns the following week jaundiced and with continued sinus tenderness.
Case #5 Study Questions
Describe these LFTs What is dominant pattern of abnormality? How would you classify the magnitude?
What is the differential diagnosis? How would PEX help you make a diagnosis? What tests would be ordered next and
why?
Case #5 Discussion
LFT Analysis Normal transaminases Borderline Alk Phos (slightly high for age) Normal synthetic function Significant elevation in bilirubin,
predominantly indirect fraction (when DB is <15% TB)
Dominant pattern: Pure indirect hyperbilirubinemia without cholestasis
Case #5 Discussion
Unconjugated hyperbilirubinemia
Increased bilirubin production*
Extravascular hemolysis
Extravasation of blood into tissues
Intravascular hemolysis
Dyserythropoiesis
Impaired hepatic bilirubin uptake
Congestive heart failure
Portosystemic shunts
Some patients with Gilbert's syndrome
Certain drugs - rifampin, probenecid flavaspadic acid, bunamiodyl
Impaired bilirubin conjugation
Crigler-Najjar syndrome type I and II
Gilbert's syndrome
Neonates
Hyperthyroidism
Ethinyl estradiol
Liver diseases - chronic persistent hepatitis, advanced cirrhosis, Wilson's disease
•Based on the history, the differential diagnosis is PCN induced hemolytic anemia vs. Gilbert Syndrome
•On physical exam, pallor and splenomegaly may support the former
•Gilbert is a diagnosis of exclusion, so the next tests must exclude hemolytic anemia:
•CBC with manual smear•Haptoglobin•LDH•Warm Agglutinins
Case #5 Discussion
What if this patient had a pure DIRECT hyperbilirubinemia? Consider Dubin-Johnson Syndrome or Rotor
Syndrome These diseases rarely present in adults You should instead carefully review
medications that might cause decreased bile excretion
With a normal Alk Phos, the lesion is inside the hepatocyte. Intrabiliary pressure is not increased
Case #6
149 281 4.2 7.1
332 3.8 3.9
A 30 male with schizophrenia on depakote for several months, presented withabdominal pain and yellow eyes for two weeks. He denies changes in stool, nausea, vomiting, fever. Had normal LFTs 3 months ago.
Case #6 Study Questions
Describe these LFTs What is dominant pattern of abnormality? Classify the magnitude of each finding
A RUQ is performed that shows dilated intrahepatic, extrahepatic and pancreatic ducts. What is the differential diagnosis and the next step in management?
Case #6 Discussion
LFT analysis Moderate transaminitis Severe cholestasis (>3x ULN) Intact synthetic function A large direct hyperbilirubinemia (DB/TB >15%) Dominant Pattern: Cholestasis with obstructive
jaundice One might argue that the transaminitis is too
severe to be explained just by obstruction…consider coexisting depakote toxicity?
Case #6 Discussion
Let’s say that his GGT was high… the dfdx is extrahepatic vs. intrahepatic cholestasis
Case #6 Discussion
Case #6 Discussion
Intrahepatic
Dilation
Extra Hepatic/CBD
Dilation
Pancreatic Duct
Dilation
PBC -- -- --
PSC +/- +/-- --
Asian Cholangiopathy
+ -- --
CBD Stricture + + +/ --
Choledocholithiasis + + +/ --
Pancreatic Mass + + +
Management of Cholestasis with ductal dilation ? ERCP vs. MRCP
Case #7
28 212 4.1 7.7
22 3.0 4.2
A 28 year-old woman comes in for a refill of her oral contraceptives. She has mild scleral icterus.
Case #7 Study Questions
Describe these LFTs What is dominant pattern of
abnormality? Classify the magnitude of each finding
A RUQ is performed that shows no dilated ducts. What is the differential diagnosis and which test should follow?
Case #7 Discussion
LFT Analysis Normal Transaminases Moderate Cholestasis (<2x ULN) Normal Synthetic function Mixed Hyperbilirubinemia Dominant Pattern: Cholestasis
Perhaps some superimposed decreased bili uptake
Case #7 Discussion
What is the differential diagnosis of intrahepatic cholestasis without ductal dilation? Primary Biliary Cirrhosis Medication Infiltration
The tests that should follow are an anti-mitochondrial antibody and a liver biopsy
Some would argue a medication review and trial of discontinuation before biopsy. Others argue ERCP before liver biopsy…
Case #8
78 904 1.6 6.6
74 1.0 3.6
A 68 year-old female with CAD, HTN, pulm HTN, DM II is admitted from clinic for vague constitutional symptoms and workup of the LFTs found below. She denies recent change in medications.
Case #8 Study Questions
Describe these LFTs What is dominant pattern of
abnormality? Classify the magnitude of each finding
What is your differential diagnosis of this pattern?
Describe an appropriate diagnostic plan
Case #8 Discussion
LFT Analysis Mild transaminitis (2x ULN) Extremely high Alkaline phosphatase Grossly intact synthetic function Mixed Hyperbilirubinemia suggestive of
intrahepatic process Dominant Pattern: Cholestasis out of
proportion to hyperbilirubinemia
Case #8 Discussion
Followup – Ultrasound and AMA negative. MRCP with patchy areas of necrosis
Biopsy – granulomatous infiltration that was negative for culture and AFB… DX Sarcoid
An Alk Phos approaching 1000 begins to suggests an infiltrative process Liver Mets Granuloma
Cholestasis Review
Case #9
47 87 0.6 11
51 0.2 4.2
A 63 year-old African American Male with diabetes presents to your clinic for the first time complaining of back pain
Case #9 Study Questions
Describe these LFTs What is dominant pattern of abnormality? Classify the magnitude of each finding
What is the differential diagnosis of this lab abnormality? What is the usual next test?
Which diagnosis fits best with this vignette?
Case #9 Discussion
LFT analysis Mild elevation in transminases (unknown
time course) No evidence of cholestasis Normal synthetic function Elevated total protein and elevated TP –
Alb gap (normal is around 4) Dominant Pattern: Paraproteinemia Next Test…
SPEP, UPEP +/-- Immunofixation
Case #9: Dfdx of gammopathy
Multiple Myeloma MGUS Waldenstrom’s
Macroglobulinemia
Amyloidosis B-cell malignancy
HIV Viral hepatitis Liver disease Connective tissue
disease Autoimmune
Hepatitis
Monoclonal Gammopathy Polyclonal Gammopathy
Case #9 Discussion
Alpha-1 fraction= alpha-1 antitrypsin, thyroid binding globulin.
Alpha-2 fraction= ceruloplasm, haptoglobin.
Beta-1= tranferrin Beta-2= beta-lipoprotein [IgA, IgM, even IgG at times].
Between Beta and Gamma= CRP, fibrinogen.
Gamma= immunoglobulins
Case #9 Discussion
Total Protein is useful as a crude marker of inflammatory state and nutritional status
Albumin will decrease in: Cirrhosis Malnutrition Protein-losing enteropathy Nephrotic syndrome Dilution with crystalloid
A word on medication review Although tedious, it is worthwhile to
carefully review medication lists with regard to when they were started
We hope this module has demonstrated how medication iatrogenosis intersects with liver injury and abnormal LFTs at every turn
Costly, time-consuming, invasive workups can be avoided with a careful review of medications
Summary
Define each abnormality and grade its severity Synthesize these findings into a predominant
pattern Leave bilirubin for the end as it is less
important in defining the predominant pattern In rare circumstances, you will identify pure
hyperbilirubinemia without cholestasis Do not forget to scan the total protein MEDS, MEDS, MEDS (search DILI in uptodate)