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)