The document discusses several cases presenting with abnormal liver function tests (LFTs). Case 1 shows a mild isolated transaminitis. Case 2 involves severe hepatocellular injury and mild cholestasis in an alcoholic patient. Case 3 examines LFT patterns in an alcoholic cirrhotic with possible alcoholic hepatitis.

1. LFT MODULE Department of Medicine Chief Residents

2. 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

3. 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

4. Representation of LFTs AST A Φ TB TP ALT DB Alb

5. Normal Values <35 30-120 <1.0 6-8 <35 <0.4 4-6

6. Case #1 A 45 year-old male presents to your Bellevue clinic to establish care. He has not seen 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 the LFTs below: 77 85 0.6 7.8 71 0.2 4.1

7. 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)?

8. Case #1 Discussion LFT analysis: This patient has an isolated mild transaminitis (2-3x ULN) ALT > AST Differential Diagnosis of Mild Transaminitis I ngestion: Alcohol and Medications I nfection: Hep B and C I mmune: Autoimmune Hepatitis I nherited: Wilson’s Dz, Hemochromatosis BM I : Hepatic Steatosis

9. 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

10. 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?

11. Case #2 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. 1218 191 3.8 7.8 1055 1.6 3.6

12. 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?

13. 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

14. 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)

15. 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

16. Case #2 Discussion

17. Case #3 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. 221 135 4.1 6.2 103 2.2 3.2

18. 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?

19. 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

20. 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

21. 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

22. Case #3 Discussion What clinical information is needed to judge the severity of his cirrhosis? Child-Pugh Class Question: In what situations is it important to know a patient’s Child-Pugh class?

23. Transaminitis Summary

24. 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

25. Case #4 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. 25 213 1.1 8.2 18 0.3 3.8

26. 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?

27. 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

28. Case #4 Discussion

29. Case #4 Discussion Let’s say that her GGT was high… the dfdx is extrahepatic vs. intrahepatic cholestasis

30. 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

31. Case #4 Discussion 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 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

32. Case #5 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. 21 115 3.9 7.5 24 0.4 4.1

33. 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?

34. 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

35. Case #5 Discussion 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 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

36. 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

37. Case #6 A 30 male with schizophrenia on depakote for several months, presented with abdominal pain and yellow eyes for two weeks. He denies changes in stool, nausea, vomiting, fever. Had normal LFTs 3 months ago. 149 281 4.2 7.1 332 3.8 3.9

38. 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?

39. 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?

40. Case #6 Discussion Let’s say that his GGT was high… the dfdx is extrahepatic vs. intrahepatic cholestasis

41. Case #6 Discussion

42. Case #6 Discussion Management of Cholestasis with ductal dilation ? ERCP vs. MRCP Intrahepatic Dilation Extra Hepatic/CBD Dilation Pancreatic Duct Dilation PBC -- -- -- PSC +/- +/-- -- Asian Cholangiopathy + -- -- CBD Stricture + + +/ -- Choledocholithiasis + + +/ -- Pancreatic Mass + + +

43. Case #7 A 28 year-old woman comes in for a refill of her oral contraceptives. She has mild scleral icterus. 28 212 4.1 7.7 22 3.0 4.2

44. 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?

45. 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

46. 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…

47. Case #8 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. 78 904 1.6 6.6 74 1.0 3.6

48. 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

49. 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

50. 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

51. Cholestasis Review

52. Case #9 A 63 year-old African American Male with diabetes presents to your clinic for the first time complaining of back pain 47 87 0.6 11 51 0.2 4.2

53. 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?

54. 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

55. 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

56. 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

57. 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

58. 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

59. 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)