Approach to the Patients with Jaundice

Dr Suresh Kubavat MD (Internal Medicine) Consultant Physician

Shradha Arogyamandir - Junagadh

9427257977

Gross Hepatic Anatomy

Gross Hepatic Anatomy

Liver Histological Structure

Liver Histological Structure

Functions of the Liver

1.Metabolism
Fats ,Proteins,Carbohydrates,Hormones

2.Storage (as Glycogen) 3.Interconversion=Glucose-Fat-Amino acids 4.Production:Fatty acids,Triglycerides,Phos -pholipids,ketones,Cholesterol,Albumin, Fibrinogen 5.Exocrine:Bile-Bilirubin-Helps digestion 6.Detoxification of ciculating toxins. 7. Drug metabolism and excretion. 8. Removal of particulate matters-Kupffer cells

Normal Bile Physiology

300mg bile/day 2 roles: 1. excretion 2. emulsification of fat Water (98%) Bile Salts Bile pigments (Bilirubin) Fatty Acids

Lecithin (Fat emulsifier,Cell protector)

Cholesterol

Na,K,Ca,Cl,Hco3

Normal Bilirubin Metabolism

Bile:300mg/Day-80% from aged dying RBCs
-20% from premature destruction in BM HemoglobinHeme + Globin HemeBiliverdin+CO+Iron Biliverdin(Water insoluble)Binds with Albumin(becomes

water soluble)Liver:unconj bil taken up by hepatocytes

conjugates to glucuronic acidBileexcr to intestine goes to terminal ilium+colonbecomes unconjugated

converted to urobilinogen80-90% excreted in faeces

as urobilins+10-20% absorbed thru intestineportal v. LiverReexcreted A small fraction escapes hepatic uptake excr in urine

Pathophysiology
Jaundice = Bilirubin staining of tissue @ level greater than 3 Mechanisms:
production of bilirubin (Hemolysis) hepatocyte transport conjugation Impaired excretion of bilirubin(Hepatitis,drugs,sepsis, Dubin-Johnson ) Impaired delivery of bilirubin into intestine

surgically relevant jaundice or obstructive jaundice

Cholestasis refers to the latter two, impaired excretion and obstructive jaundice

Definition of Jaundice
Jaundice is yellow discoloration of the sclera, skin and mucous membranes resulting from accumulation of bilirubin. Normal bilirubin levels are 0.4+0.2 mg per dl, with > 95% unconjugated. Hyperbilirubinemia is separated into two classes : unconjugated (> 80% of total bilirubin) and conjugated (>30 % of total bilirubin)

Algorithm for PT with jaundice.

History+Physical exam+Lab tests

Isolated elevation of the Bilirubin

Bilirubin & other liver tests elevated Indirect hyperbilirubinemia Drugs Rifampicin

Direct hyperbilirubinemia

Inherited disorders 1. Dubin Johnson Syndrome 2. Rotors Syndrome

Inherited Disorders 1. Gilberts Syndrome 2. CriglerNajjar Syndromes

Hemolytic Disorders-Sphero,Ellipto,G6PD,Sickle,immune Ineffective erythropoiesis-Iron,Folate,B12 def,Thallesemia.

ALGORITHM CONTINUED
Bilirubin & other liver tests elevated

Hepatocellular Pattern

Cholestatic Pattern

SGPT/OT elevated out of proportion to Alkaline phosphatase

Alkaline phosphatase elevated out of proportion to SGPT/OT

Hepatocellular Pattern
1. Viral Serologies Hepatitis A IgM Hepatitis B Surface Antigen & core antibody (IgM) Hepatitis C RNA 2. Toxicology screen Acetaminophen level 3. Ceruloplasmin (If Pt < 40) 4. ANA, SMA, LKM(Liver Kidney Microsomal Antibody), SPEP( Serum protein electrophoresis) If negative Liver Biopsy

Additional Virologic Testing CMV DNA, EBV capsid antigen Hepatitis D antibody(If indicated) Hepatitis E IgM(If indicated)

If negative

Cholestatic Pattern
Dilated Ducts Extra hepatic cholestasis CT/ERCP Negative MRCP/Liver Biopsy Serologic testing AMA Hepatitis Serologies Hepatitis A CMV, EBV Review Drugs Ultrasound Ducts not Dilated Intra hepatic cholestasis

Liver Biopsy

AMA +ve

Prehepatic
Unconguated Bil LFTs N

Haptoglobins (a protein in blood that combines with hb to form a complex that is removed from @ by the liver) Reticulocytes
Coombs test +ve Urine urobilinogen +

Hepatic
ALT(SGPT) ALP N or Bil Albumin INR Hepatitis serology Autoantibodies
Anti-mitochondrial PBC Anti-nuclear & antimicrosomal, Autoimmune hepatitis

Caeruloplasmin
Wilsons

-Globulins
Cirrhosis esp autoimmune

Transferrin
Haemochromatosis

-foetoprotein, FP
HCC(Hepato cellula Carcinoma) in cirrhosis

Hepatic Causes
Viral Hepatitis : A,B,C,D,E / EBV / CMV /Herpes Simplex.
Alcohol Drug toxicity : Predictable: Paracetamol Unpredictable:INH Environmental toxins : Vinyl chloride (PVC)Ca

Jamaica Bush Tea

Kava Kava Wild mushrooms Wilsons disease Autoimmune hepatitis.

Alcoholic Liver Disease

The history is the key 60 grams-aprox 60ml/day

Gynecomastia,

parotids, Dupuytrens

Lab clues: SGOT/SGPT > 2, SGOT < 300 Alcoholic hepatitis:Anorexia, fever, jaundice, hepatomegaly Treatment: Abstinence,Nutrition

Prednisolone (Antiinflamatory) Pentoxifylline (Decreases the risk of developing hepatorenal syndrome and thus diminishes mortality.

Alcoholic Liver Disease

Discriminant Function Formula: DF =[4.6 x (Pt PT control PT)] + T.Bili Consider treatment for DF > 32 Prednisolone 40 mg/day x 28 days
contraindications: infection, renal failure, GIB

Pentoxifylline 400 mg PO tid x 28 days

Autoimmune Hepatitis
Widely variable clinical presentations
Asymptomatic LFT abnormality (ALT and AST)
Severe hepatitis with jaundice Cirrhosis and complications of portal HTN

Often associated with other autoimmune dz

Diagnosis:
Compatible clinical presentation

ANA or ASMA with titer 1:80 or greater

IgG > 1.5 upper limits of normal Liver biopsy: portal lymphocytes + plasma cells

Acetaminophen Toxicity
Safe Dose is < 4 gms/Day for an adult. Danger dosages (70 kg patient) Toxicity possible > 10 gm Severe toxicity certain > 25 gm

Lower doses potentially hepatotoxic in:

Chronic alcoholics Malnutrition or fasting

Dilantin, Tegretol, phenobarbital, INH, rifampin

-Antidote N acetyl cysteine within 16 Hrs

Post - hepatic
ALT(SGPT) N or ALP(Alk PO4) Bil

INR
CEA, Ca19.9
Pancreatic & cholangio Ca

Cholestatic Jaundice-Intrahepatic
Chronic cholestasis
Viral : B & C Fibrosing cholestatic HepA,EBV,CMV Alcoholic hepatitis Chlorpromazine, Prochlorperzine. Primary Biliary Cirrhosis Prim Scler Cholangitis

Drug Toxicity :
Pure cholestasisAnabolic Steroids

Vanishing Bile duct Syn

Inherited progr familial intrahepatic cholestasis

Contraceptives
Cholestatic Hepatitis Chlorpromazine

Benign recur cholestas

Cholestasis of Preg TPN

Erythromycin

Non hepatobil sepsis

Cholestatic Jaundice-Intrahepatic- cont

Benign Post op cholest Paraneoplastic Syndr Venoocclusive Dis Infiltrative diseases TB,Lymphoma,sarcoid

Cholestatic Jaundice-Extrahepatic
A. Malignant
Cholangiocarcinoma,Pancreatic ca, Ca-GB, Ampulla Ca, Malig involvement of porta hepatis lymph nodes. B. Benign

Choledocolithiasis,Post op biliary stricture,

Primary sclerosing cholangitis, Chronic pancreatitis, AIDS Cholangiopathy,

Mirizzi Syndrome:stricture of common hepatic duct

Parasitic disease- Ascariasis.

Obstructive Jaundice
CBD stones (choledocholithiasis) vs. tumor Clinical features favoring CBD stones:
Age < 45
Biliary colic Fever

Transient spike in AST or amylase

Clinical features favoring cancer:

Painless jaundice Weight loss Palpable gallbladder Bilirubin > 10

Ascending Cholangitis
Pus under pressure

Charcots triad: fever, jaundice, RUQ pain

All 3 present in 70% of patients, but fever > 95% May also present as confusion or hypotension

Most frequent causative organisms:

E. Coli, Klebsiella, Enterobacter, Enterococcus anaerobes are rare and usually post-surgical

Treatment:
Antibiotics: Levaquin, Zosyn, meropenem ERCP with biliary drainage

Ascending Cholangitis Indications for Urgent ERCP Persistent abdominal pain

Hypotension despite adequate IVF Fever > 102 Mental confusion Failure to improve after 12 hours of antibiotics and supportive care

Obstructive Jaundice
Malignant Causes

Cancer of the Pancreas

Cancer of the Bile Ducts (Cholangiocarcinoma) Ampullary Tumors

Portal Lymphadenopathy

 Cholestatic liver disease (ALP)

Primary Biliary Cirrhosis

Most common symptoms: pruritus and fatigue Many patients asx, and dx by abnormal LFT Female:male ratio 9:1

Diagnosis:
Compatible clinical presentation AMA titer 1:80 or greater (95% sens/spec) IgM > 1.5 upper limits of normal Liver biopsy: bile duct destruction

Treatment: Ursodeoxycholic acid 15 mg/kg

Primary Sclerosing Cholangitis

Cholestatic liver disease (ALP)
Inflammation of large bile ducts

90% associated with IBD

but only 5% of IBD patients get PSC Diagnosis: ERCP (now MRCP) No autoantibodies, no elevated globulins Biopsy: concentric fibrosis around bile ducts Cholangiocarcinoma: 10-15% lifetime risk Treatment: Liver Transplantation

Diagnosis of Immune-Mediated Liver Disease

LFT Serology Quantitative
Immunoglobulins

Biopsy
Portal inflammation Plasmacytes Piecemeal necrosis Bile duct destruction granulomas Periductal concentric fibrosis

AIH

SGPT

ANA ASMA AMA

IgG

PBC

ALP

IgM normal

PSC

ALP

none

Common causes of Jaundice

Hepatitis

Obstructive jaundice
Primary liver cancer

Liver secondaries
Cirrhosis Haemolysis Gilberts syndrome Septicaemia

Unusual Causes of Jaundice

Ischemic hepatitis Congestive hepatopathy

Wilsons disease
AIDS cholangiopathy Amanita phalloides (mushrooms) Jamaican bush tea Infiltrative diseases of the liver
Amyloidosis
Sarcoidosis Malignancy: lymphoma, metastatic dz

Wilsons Disease
Autosomal recessive copper metabolism
Chronic hepatitis or fulminant hepatitis

Associated clinical features:

Neuropsychiatric disease Hemolytic anemia Physical exam: Kayser-Fleischer rings Diagnosis: ceruloplasmin, urinary Cu Treatment: d-penicillamine

LFTs and urine summary

Blood SGPT Prehepatic Hepatic N N or ALP N N or Bil Urine
Urobilinogen

Bilirubin absent Present Present

Present N absent

Posthepatic

Broad Differential Diagnosis

production transport or conjugation Gilberts Crigler-Najarr Neonatal Cirrhosis Impaired excretion Rotors Biliary obstruction

Unconjugate Unconjugate Conjugated

Hemolysis Transfusions Txfusion rxn Sepsis

Conjugated
CH/CBD stone

DubinJohnson Stricture Cancer Cirrhosis Cancer Chronic pancreatitis

Burns
Hgb-opathies

Hepatitis

Hepatitis

PSC

Drug inhibition Amyloidosis Pregnancy

Causes of Jaundice
Unconjugated hyperbilirubinemia
Hemolysis Glucose-6-phosphate deficiency Medications Bilirubin overproduction Ineffective erythropoiesis Large hematoma Pulmonary embolism with infarction Neonatal causes Physiologic jaundice Breast milk jaundice Uridine diphosphate glucuronosyltransferase deficiencies Gillberts syndrome Crigler-Najjar syndrome ( I and II)

Miscellaneous causes Hypothyroidism Thyrotoxicosis Fasting

Causes of Jaundice
Conjugated hyperbilirubinemia
Congenital causes Rotors syndrome Dubin-Johnson syndrome Choledochal cysts

Familial disorders Benign recurrent intrahepatic cholestasis Cholestasis of pregnancy

Hepatocellular defects Ethanol abuse Viral infection Cholestatic syndromes Primary billiary cirrhosis Primary sclerosing cholangitis Billiary obstruction Pancreatic disease

Systemic disease
Infiltrative disorders Postoperative complications Renal disease Sepsis Medications

History
Oral Exposure:Alcohol,Chemicals,Rx Med,OTC Med, Complementary med,Alternative Med,Contamin food. Parenteral Exposure:IV inj,Transfusions, Tattoo(Hep C), Intranasal drugs(Hep C) Sexual exposure(Hep B). Exposure to Endemic area-Travel history(Hep A). Professional Exposure:Drs,Paramedics(Hep B+C). Occupational exposure to Hepatotoxins.

Hepatotoxins
Antimony Arsenic Barium Bismuth. Cadmium. Molibdinum Nickel. Phosphorus. Selenium. Thallium.

Chromium.
Copper. Iron. Lead. Manganese.

Tin.

Occupational Exposure
Occupation
Artificial pearls Air Pilots, Hanger workers

Maker

Worker

User

Cement,Rubber,Plastic,Leather
Chemical,Pharma industry Color,Dye,Insecticides Glass,Ink,Paint,Perfumes Dry cleaners,Varnish,Waterproofer Metal polish Refrigeration,Printers Soap,Thermometer,Wax Tobacco denicotisers.

History for the Jaundice Patients

Related to viral hepatitis Preceding arthralgia/myalgia Blood transfusions B Intravenous drug use B Needle stick exposure B Sexual practices HIV hepatitis Contact with jaundiced persons B Work in renal dialysis units B Surgeons in trauma units - B exposed to IV drug users - B Shared razors/tooth brushes - B Body piercing (ears,nose) -B Tattoos -B

SYMPTOMS
Fever- Low gr to High grade Low gr-hepatits

High gr + RUQ abd painCholedocolithiasis,Ascending colangitis.

Arthralgia,Myalgia Rash Anorexia, Wt loss Avulsion to tobacco Abd Pain-Mild/Severe, Acute/Chronic Pruritus Change in urine,stool colour

Physical Examination Laennecs(Alcohol ic)+other cirrhosis

Spider nevi,palmar erythema,gynecomastia,caput medusae,Dupuytrens contracture,Enlaged parotids,testicular atrophy,R.pl effusion,Enlarged L.lobe of liver,Ascites,Enl spleen.

Abd.Malignancy
R.Sided Heart failure
Viral Hepatitis,Amyloidosis, R.Heart failure.

Enl supracl node(Virchows node),Periumbilical node(sister marry josephs node),Nodular hard liver.

Jugular venous distention, edema, Enlarged tender liver. Enlarged tender liver,

Cholecystitis Acute Cholangitis

Cirrhosis Malignancy

Murphys sign :Severe RUQ tenderness with resp arrest in inspiration.

Ascites+Jaundice.

Spider Nevi

Palmar Erythema

Gynecomastia

Caput Medusae

Dupuytrens contracture

Virchows Node

Sister Marry Josephs Nodule.

Gross specimen of cirrhosis of the liver

Evaluation of the Jaundiced Patient PHYSICAL EXAM

BP/HR/Temp Mental status Asterixis

Spider angiomata Hyperpigmentation Kayser-Fleischer rings

Abd tenderness
Liver size

Xanthomas
Gynecomastia Left supraclavicular adenopathy (Virchows node)

Splenomegaly
Ascites

Edema

Common causes of Jaundice and relevant investigations

Acute hepatitis

Hepatitis serology
HBsAg, IgM anti-HBc, HBeAg, Anti-HBe IgM anti HAV, Anti Delta antibody Anti HCV

Ig M anti HEV
IgM EBV, IgM CMV, IgM Lepto antibody Pancreatic/biliary disease

Ultrasonography
Endoscopic retrograde cholangio-pancreatography Percutaneous transhepatic cholangiography CT Scanning MRI-MRCP

Common causes of Jaundice and relevant investigations - contd

Malignancy Liver biopsy Alpha fetoprotein Cirrhosis Liver biopsy

Immunoglobulins
Auto antibodies Iron studies Serum, urine and liver copper; serum ceruloplasmin Alpha 1 antitrypsin

Common causes of Jaundice and relevant investigations - contd

Haemolysis
Reticulocyte count
Haptoglobin Direct and indirect Coombs Test G-6-P-D level

Gilberts Syndrome
Increase in unconjugated bilirubin following 2-3 days on 1 400 calorie diet

Tips on Interpretation of Lab Tests

SGPT?OT > ALP Hepatocellular Process

ALP > SGPT/ OT Cholestatic Process Bilirubin : Increased in both but if D>I : Cholestatic I>D : Prehepatic.

D=I : Hepatocellular
.Albumin if normal Acute cause like Hepatits,Choledocolithiasis. Prothrombin time: chronic cause + Signific hepatocell dysfunction. If PT improves after inj Vit K Good liver functions. If PT doesnt improve after KSev hepatocellular injury.

Haemolytic anaemia
Mechanism
Abnormal red cell membrane

Examples
Hereditary spherocytosis Drug e.g. Sulphonamides sulphonylureas, alphamethyldopa, levodopa Primary immune deficiency
Sickle cell , Thalassaemia Cardiac haemolysis (prosthetic valves) Microangiopathic haemolysis

Rigid red cell membrane Trauma to red cells

Commonly used drugs causing jaundice

Drugs causing hepatitis Amitriptyline Isoniazid Erythromycin (estolate) Nitrofurantoin Paracetamol (more than 4g a day) Ferrous sulphate overdose Halothane Drugs causing cholestasis Oral contraceptives Chlorpromazine Haloperidol Chlorpropamide

Causes of postoperative jaundice

Hypertension/cardiac failure Post-transfusion hepatitis

Drugs including anaesthetics, particularly halothane on second exposure

Unmasked chronic liver disease Unmasked biliary tract disease Pulmonary embolism Acalculus/acute cholecystitis

Transfusion load/haemolysis post cardiopulmonary bypass pump

Cholestasis following major abdominal surgery & TPN

Sepsis (pneumonia,urinary tract infection)

Liver biopsy- indications

Assessment of abnormal liver function tests Diagnosis and prognosis of chronic hepatitis and/or cirrhosis Confirmation and prognosis of alcoholic liver disease Detection of systemic disorders involving the liver, including fever of unknown origin Assessment and severity of drug inducted liver injury Confirmation of suspected hepatic malignancy, primary or metastatic Confirmation of multisystem infiltrative disorders Screening of relatives of patients with familial disease Tissue of culture Evaluation of response to therapies for liver disease (e.g. Wilsons disease, hemochromatosis, autoimmune hepatitis, chronic viral hepatitis)

Exclusion of graft rejection, reinfection, or ischemia after liver transplant

Liver biopsy- contra-indications

Absolute Severe coagulopathy PT > 3 seconds prolonged Platelets < 60 000/mm Abnormal bleeding time Suspected echinococcal disease Presumed hemangioma Uncooperative patient Relative Ascites

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?

Evaluation of the Jaundiced Patient LAB EVALUATION

AST-ALT-ALP Bilirubin total/indirect Albumin

Ammonia Viral serologies ANA-ASMAAMA Quantitative Ig Ceruloplasmin Iron profile Blood cultures

INR
Glucose

Na-K-PO4, acid-base
Acetaminophen level

CBC/plt

Drugs causing high SGPT/OT

Aspirin,PCM Statins

Brufen,Naproxen
Phenytoin,Sod valproate Carbamazepine Tetra,Sulpha,TMP INH,NFT,Fluconaz

Niacin
Amiodarone

Hydralazine
Quinidine Tricyclic Antidep

Other disease causing abn OT/PT

Hemachromatosis

Wilsons disease
Alpha 1 antitrypsin def(with emphysema)

Celiac sprue
Crohns disease Ulcerative colitis

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

Utility of Liver Function Test

Sensitive and non invasive method of screening for the presence of liver dysfunction
The pattern of test abnormalities may allow to recognize type of liver disorder To assess the severity of liver disorder To follow the course of disease

THANK YOU ALL !

Thanks to my son Vishwas for helping me in preparing this PPT presentation !