elevated lft

1. Approach to a patient
with jaundice
Dr. Hazem Al-Ashhab

2. Jaundice
• Yellow discoloration of skin & sclera due to
excess serum bilirubin. >40umol/l,
(3mg/dl)
• Conjugated & Unconjugated types
• Obstructive & Non Obstructive (clinical)
• Pre-Hepatic, Hepatic & Post Hepatic
types
• Jaundice - Not necessarily liver disease *

3. Bilirubin
Metabolism
•Blood
• Conjugated &
Unconjugated
•Urine – Urobilinogen
•Stool – Stercobilin

4. Common Causes of Jaundice
• Pre Hepatic (Acholuric) - Hemolytic
– Unconjugated/Indirect Bil, pale urine
• Hepatic – Viral, alcohol, toxins, drugs
– Liver damage - unconjugated
– Swelling, canalicular obstruction -
Conjugated
• Post Hepatic (Obstructive) – Stone,
tumor
– Conjugated/Direct Bil, High colored urine,

5. Critical Questions in the Evaluation
of the Jaundiced Patient
• Acute vs. Chronic Liver Disease
• Hepatocellular vs. Cholestatic
– Biliary Obstruction vs. Intrahepatic Cholestasis
• Fever
– Could the patient have ascending cholangitis?
• Encephalopathy
– Could the patient have fulminant hepatic failure?

6. Evaluation of the Jaundiced Patient
HISTORY
• Pain
• Fever
• Confusion
• Weight loss
• Sex, drugs, R&R
• Alcohol
• Medications
• pruritus
• malaise, myalgias
• dark urine
• abdominal girth
• edema
• other autoimmune dz
• HIV status
• prior biliary surgery
• family history liver dz

7. Evaluation of the Jaundiced Patient
PHYSICAL EXAM
• BP/HR/Temp
• Mental status
• Asterixis
• Abd tenderness
• Liver size
• Splenomegaly
• Ascites
• Edema
• Spider angiomata
• Hyperpigmentation
• Kayser-Fleischer rings
• Xanthomas
• Gynecomastia
• Left supraclavicular
adenopathy
(Virchow’s node)

8. Evaluation of the Jaundiced Patient
LAB EVALUATION
• AST-ALT-ALP
• Bilirubin – total/indirect
• Albumin
• INR
• Glucose
• Na-K-PO4, acid-base
• Acetaminophen level
• CBC/plt
• Ammonia
• Viral serologies
• ANA-ASMA-AMA
• Quantitative Ig
• Ceruloplasmin
• Iron profile
• Blood cultures

9. Evaluation of the Jaundiced Patient
• Ultrasound:
– More sensitive than CT for gallbladder stones
– Equally sensitive for dilated ducts
– Portable, cheap, no radiation, no IV contrast
• CT:
– Better imaging of the pancreas and abdomen
• MRCP:
– Imaging of biliary tree comparable to ERCP
• ERCP:
– Therapeutic intervention for stones
– Brushing and biopsy for malignancy

10. New Onset Jaundice
• Viral hepatitis
• Alcoholic liver disease
• Autoimmune hepatitis
• Medication-induced liver disease
• Common bile duct stones
• Pancreatic cancer
• Primary Biliary Cirrhosis (PBC)
• Primary Sclerosing Cholangitis (PSC)

11. Jaundiced Emergencies
• Acetaminophen Toxicity
• Fulminant Hepatic Failure
• Ascending Cholangitis

12. Jaundice Unrelated to
Intrinsic Liver Disease
• Hemolysis (usually T. bili < 4)
• Massive Transfusion
• Resorption of Hematoma
• Ineffective Erythropoesis
• Disorders of Conjugation
–Gilbert’s syndrome
• Intrahepatic Cholestasis
–Sepsis, TPN, Post-operation

13. HBV Serology
HBSAg HBcAb
IgM
HBcAb
IgG
HBSAb
Acute HBV
+ + - -
Resolved HBV
- - + +
Chronic HBV
+ - + -
HBV vaccinated
- - - +

16. Natural History of Chronic Liver
Disease
Chronic liver
disease
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Development of complications:
· Variceal hemorrhage
· Ascites
· Encephalopathy
· Jaundice

18. Diagnosis of cirrhosis
• clinical+laboratory+radiologic+liver biopsy

19. In Whom Should We Suspect
Cirrhosis?
• Any patient with chronic liver disease
– Chronic abnormal aminotransferases and/or
alkaline phosphatase.
• Physical exam findings
– Stigmata of chronic liver disease (muscle
– wasting, vascular spiders, palmar erythema)
– Palpable left lobe of the liver
– Small liver span
– Splenomegaly
– Signs of decompensation (jaundice,
ascites,asterixis)

20. Jaundice

21. Yellow hands on top, red palms
underneath - a sign of liver damage

22. Ascitis in Cirrhosis

23. Gynaecomastia in cirrhosis

29. In Whom Should We Suspect
Cirrhosis?
• Laboratory
– Liver insufficiency
• Low albumin (< 3.8 g/dL)
• Prolonged prothrombin time (INR > 1.3)
• High bilirubin (> 1.5 mg/dL)
– Portal hypertension
• Low platelet count (< 175 x1000/ml)
– AST / ALT ratio > 1

31. CT Scan in Cirrhosis

33. INTRODUCTION
• Idiosyncratic (unpredictable) drug-induced
liver injury is one of the most challenging
liver disorders faced by hepatologists.
• DILI is the leading cause of acute liver
failure (ALF) in the United States.
• It is also the most common single adverse
event that has led to withdrawal of drugs
from the marketplace, and failure of
implicated drugs to obtain U.S FDA
approval.
• DILI is traditionally classified as intrinsic (or
direct) vs. idiosyncratic.

34. • Intrinsic DILI is typically dose-related
and occurs in a large proportion of
individuals exposed to the drug so it is
predictable.
• Idiosyncratic DILI occurs in only a
small proportion of exposed individuals
(unpredictable) with variable latency to
onset of days to weeks.
• In both types the chemical
characteristics of the drug are
important, particularly lipophilicity and
drug biotransformation.

35. Risk Factors for DILI
• AGE:
❖ 5 times higher incidence in patients over 70 years than
those between 15 and 29 years. (Population based Icelandic study)
❖ Cholestatic DILI is more common in the elderly.
❖ Valproic acid induced liver injury is more common in
children.
• Women may be more susceptible to DILI than men,
which in part due to their generally smaller size.
• Alcohol use disorder and malnutrition predispose DILI in
some cases.

36. Burden of DILI
• In western countries, acetaminophen (APAP)-
related liver injury remains one of the leading
causes of DILI.
• Annual incidence of DILI ranges from 2.3-
13.9/100,000 inhabitants in population-based
studies from Europe.
• Most of the cases reported in the western
countries are DILI secondary to prescription
medications.
• Traditional/complementary and dietary
supplements are the main causative agents of
DILI in Asia.

37. Defining DILI
• Liver injury is recognized by abnormal liver
biochemistries with or without associated clinical
symptoms.
• The updated Roussel Uclaf Causality Assessment
Method (RUCAM) uses an ALT >5-times ULN and/or
ALP >2-times ULN to identify liver injury.
• However, lesser sustained elevations, rapidly rising
tests, or any elevation combined with signs of liver
dysfunction are clinically significant and worthy of
investigation.

38. Type of
classification
Clinical laboratory
Hepatocellular
Cholestatic
Mixed
hepatocellular/cholestatic
Mechanism of
hepatotoxicity
Direct hepatotoxicity
Idiosyncratic
• Immune-mediated
• Metabolic
Histologic findings
Cellular necrosis or
apoptosis
Cholestasis
Steatosis
Fibrosis
Phospholipidosis
Granulomatous
Sinusoidal obstruction

39. Drugs associated with intrinsic vs.
idiosyncratic DILI.
Intrinsic Idiosyncratic
Acetaminoph
en
Allopurinol Leflunamide
Amiodarone Amiodarone Lisinopril
Anabolic
steroids
Amoxicillin-
clavulanate
Methyldopa
Cholestyramin
e
Bosentan Nitrofurantoin
Cyclosporine Dantrolene Phenytoin
Valproic acid Diclofenac Pyrazinamide
HAART drugs Fenofibrate Propylthiouracil
Heparins Flucloxacillin Statins
Nicotinic acid Halothane Sulfonamides
Statins Isoniazid Terbinafine
Tacrine Ketoconazole Trovafloxacin

40. Recognizing the pattern of liver injury at the
initial presentation is vital.
The R-ratio can identify the injury pattern;
Defined as the ratio of serum ALT to ALP values,
both expressed as multiples of ULN.
Should be obtained at the onset of injury.
R-ratio of >5 indicates hepatocellular injury.
<2 indicates cholestatic injury.
2-5 indicates mixed injury.

41. DRUGS AND PATTERN OF
LIVER INJURY
• Hepatocellular Cholestatic Mixed
• • APAP
• • Isoniazid • Amoxicillin/clavulanate • Azathioprine
• • Macrolides • Trimethoprim/ sulfamethoxazole • Flavocoxid
• • Minocycline • Anabolic/androgen containing steroids • Sulfasalazine
• • Nitrofurantoin • Chlorpromazine • Phenytoin
• • Inhaled anesthetics • Azathioprine • Carbamazepine
• • Phenytoin • Phenytoin • Allopurinol
• • Carbamazepine • Fluoroquinolones • Amiodarone
• • Valproate • Carbamazepine • Fluoroquinolone
• • Sulfonamides • Amiodarone
• • Amiodarone • Sulfasalazine
• • Allopurinol
• • NSAIDs
• • Fluoroquinolones
Hig
h
risk
Lo
w

42. MANAGEMENT OF
DILI
• The primary treatment for DILI is withdrawal of the
offending drug.
• Early recognition of drug toxicity is important to
permit assessment of severity and monitoring for
acute liver failure.
• Few specific therapies have been shown to be
beneficial in clinical trials.
• Two exceptions are the use of N-acetylcysteine
for acetaminophen toxicity and L-carnitine for cases
of valproic acid overdose.

43. STEROIDS ?
(UpToDate authors)
Glucocorticoids are of
unproven benefit for most
forms of drug
hepatotoxicity.
Our practice is to give glucocorticoids to
patients with:
• Hypersensitivity reactions.
• Progressive cholestasis despite drug
withdrawal.
• Biopsy features that resemble those seen in
autoimmune hepatitis.

44. MANAGEMENT OF DILI
• In patients with cholestatic liver disease and pruritus,
treatment with a bile acid sequestrant may relieve the
pruritus.
• Patients should be followed by serial biochemical
measurements until the liver tests return to normal.
• Hepatology consultation should be considered if
there is concern that the patient may be developing
acute liver failure, if there are signs of chronic liver
disease, or if the diagnosis remains uncertain after
an initial evaluation.
• Patients with evidence of ALF should be transferred
to a transplant center early in the course of the
illness.

45. PROGNOSIS
• The overall prognosis for purely cholestatic injury is better than
that for hepatocellular injury.
• Drug-induced acute steatosis (fatty degeneration) is uncommon
and occurs less often than chronic steatosis. Jaundice is usually
mild, and serum aminotransferases are lower than they are in
cytotoxic injury.
• The incidence of chronic DILI varies from 5%-20% in various
DILIN registries and population-based studies.
• Chronic DILI, conventionally defined as persistence of liver
enzyme elevations for more than 6 months after withdrawal of an
offending drug.
• Gradual progression to cirrhosis can be seen without any
manifestation of clinical illness (as
with amiodarone, methotrexate, or methyldopa).

46. PROGNOSIS
• The majority of patients with DILI will experience
complete recovery once the offending medication is
stopped. In the setting of cholestatic injury, jaundice
can take weeks to months to resolve.
• Factors associated with a poorer prognosis in
patients with hepatocellular injury include:
▪ ("Hy's law").
▪ Acute liver failure due to antiepileptics in children.
▪ An elevated serum creatinine.
▪ Presence of pre-existing liver disease.

47. THANK
YOU