Approach to theJaundiced Patient

Dr. Ümit Akyüz

Yeditepe University

Division of Gastroenterology

Jaundice

• A yellowing of the skin, sclerae( 공막 ), and other tissues caused by excess circulating bilirubin

Bilirubin Metabolism

• Formation: About 250 to 350 mg of bilirubin forms daily; 70 to 80% derives from the breakdown of senescent RBCs. The remaining 20 to 30% (early-labeled bilirubin) comes from other heme proteins located primarily in the bone marrow and liver. The heme moiety of Hb is degraded to iron and the intermediate product biliverdin by the enzyme heme oxygenase. Another enzyme, biliverdin reductase, converts biliverdin to bilirubin.

• Plasma transport: Because of internal hydrogen bonding, bilirubin is not water-soluble. Unconjugated (indirect-reacting) bilirubin is therefore transported in the plasma bound to albumin

• Liver uptake: Uptake of bilirubin is via active transport and is rapid

• Conjugation: Free bilirubin concentrated in the liver is conjugated with glucuronic acid to form bilirubin diglucuronide, or conjugated (direct-reacting) bilirubin. This reaction, catalyzed by the microsomal enzyme glucuronyl transferase, renders the bilirubin water-soluble

• indirect reacting bilirubin

The fraction of serum bilirubin which has not been conjugated with glucuronic acid in the liver cell; so called because it reacts with the Ehrlich diazo reagent only when alcohol is added; increased levels are found in hepatic disease and haemolytic conditions.

• Biliary excretion: Conjugated bilirubin is secreted into the bile canaliculus ( 모세담관 ) with other bile constituents. In the intestine, bacterial flora deconjugate and reduce bilirubin to compounds called stercobilinogens . The kidney can excrete bilirubin diglucuronide but not unconjugated bilirubin. This explains the dark urine typical of hepatocellular or cholestatic jaundice and the absence of urinary bile in hemolytic jaundice

• Abnormalities at any of these steps can result in jaundice. Increased formation, impaired liver uptake, or decreased conjugation can cause unconjugated hyperbilirubinemia. Impaired biliary excretion produces conjugated hyperbilirubinemia. In practice, both liver disease and biliary obstruction create multiple defects, resulting in a mixed hyperbilirubinemia

Diagnostic Approach to Jaundice

• Symptoms and Signs

-Mild jaundice without dark urine : unconjugated hyperbilirubinemia caused by hemolysis or Gilbert's syndrome rather than hepatobiliary disease

-More severe jaundice or dark urine clearly indicates a liver or biliary disorder.

-Signs of portal hypertension ( 문맥고압증 ), ascites, or skin and endocrine changes usually imply a chronic rather than an acute process

-Patients often notice dark urine before skin discoloration; thus, the onset of dark urine better indicates the duration of jaundice

-Nausea and vomiting preceding jaundice most often indicate acute hepatitis or common duct obstruction by a stone; abdominal pain or rigors favor the latter

Laboratory Findings

• Mild hyperbilirubinemia with normal aminotransferase and alkaline phosphatase levels usually reflects hemolysis or Gilbert's syndrome rather than liver disease

• Aminotransferase elevations > 500 U suggest hepatitis or an acute hypoxic episode; disproportionate increases of alkaline phosphatase suggest a cholestatic or infiltrative disorder

• Low albumin and high globulin levels indicate chronic rather than acute liver disease

DISORDERS OF BILIRUBIN METABOLISM

• Unconjugated Hyperbilirubinemia :

-Hemolysis

-Gilbert's syndrome : defects in the liver's uptake of plasma bilirubin ( 우성유전 )

-Crigler-Najjar syndrome : glucuronyl transferase deficiency

-Primary shunt hyperbilirubinemia: This rare, familial benign condition is associated with overproduction of early-labeled bilirubin.

• Noncholestatic Conjugated Hyperbilirubinemia

-Dubin-Johnson syndrome: Asymptomatic mild jaundice characterizes this rare autosomal recessive disorder. The basic defect involves impaired excretion of various organic anions as well as bilirubin, but bile salt excretion is unimpaired.

-Rotor's syndrome: This rare disorder is similar to Dubin-Johnson syndrome, but the liver is not pigmented and other subtle metabolic differences are present

• CHOLESTASIS

-A clinical and biochemical syndrome that results when bile flow is impaired

• -Etiology :Bile flow may be impaired at any point from the liver cell canaliculus to the ampulla of Vater( 바터팽대부 ) . The most common intrahepatic causes are hepatitis, drug toxicity, and alcoholic liver disease. Less common causes include primary biliary cirrhosis(담즙성간경변 ), cholestasis of pregnancy, metastatic carcinoma, and numerous uncommon disorders.The most common extrahepatic causes are a common duct stone and pancreatic cancer. Less common causes include benign stricture of the common duct (usually related to prior surgery), ductal carcinoma, pancreatitis or pancreatic pseudocyst, and sclerosing cholangitis( 경화성 담관염 )

-Pathophysiology : interference with microsomal hydroxylating enzymes, which leads to the formation of poorly soluble bile acids; impaired activity of Na+,K+-ATPase, which is necessary for canalicular bile flow; altered membrane lipid composition and fluidity; interference with the function of microfilaments (thought to be important for canalicular function); and enhanced ductular reabsorption of bile constituents. Because bile salts are needed for absorption of fat and vitamin K, impaired biliary excretion of bile salts can produce steatorrhea( 지방변 ) and hypoprothrombinemia(

저프로트롬빈혈증 ). In long-standing cholestasis (eg, primary biliary cirrhosis), concomitant Ca and vitamin D malabsorption may result in osteoporosis or osteomalacia( 골연화증 )

• Symptoms and Signs

-Jaundice, dark urine, pale stools, and generalized pruritus( 소양증 ) • Diagnosis :

-Intrahepatic and extrahepatic cholestasis must be differentiated. Intrahepatic cholestasis is suggested by symptoms of hepatitis, heavy alcohol ingestion, recent use of potentially cholestatic drugs, or signs of chronic hepatocellular disease (eg, spider nevi, splenomegaly, ascites). Extrahepatic cholestasis is suggested by biliary or pancreatic pain, rigors( 오한 ), or a palpable gallbladder.

-Laboratory tests

-Imaging studies

-Liver biopsy

• Treatment

-In intrahepatic cholestasis, treating the underlying cause usually suffices

-Extrahepatic biliary obstruction usually requires intervention: surgery, endoscopic extraction of ductal stones, or insertion of stents and drainage catheters for strictures (often malignant) or partially obstructed areas

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)

Jaundiced Emergencies

• Acetaminophen Toxicity

• Fulminant Hepatic Failure

• Ascending Cholangitis

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

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)

HBV SerologyHBSAg HBcAb

IgM

HBcAb

IgG

HBSAb

Acute HBV + + - -Resolved HBV - - + +Chronic HBV + - + -HBV vaccinated - - - +

From DL Thomas

Acute Hepatitis C

HCV RNA

Anti-HCV

0 10 20 30 40 50 60 70 80 90 100

Infection Day 0

HCV RNA Day 12

HCV Antibody Day 70

Plateau phase = 57 days

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)

Alcoholic Liver Disease• The history is the key – 60 grams/day• Gynecomastia, parotids, Dupuytren’s• Lab clues: AST/ALT > 2, MCV > 94 AST < 300• Alcoholic hepatitis:

– Anorexia, fever, jaundice, hepatomegaly– Treatment:

• Abstinence• Nutrition• Consider prednisolone or pentoxifylline

Alcoholic Liver Disease

Discriminant Function Formula:

DF = [4.6 x (PT – control)] + bilirubin

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

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)

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

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)

Drug-induced Liver Disease• Hepatocellular

– acetaminophen, INH, methyldopa, MTX

• Cholestatic– chlorpromazine, estradiol, antibiotics

• Chronic Hepatitis– methyldopa, phenytoin, macrodantin, PTU

• Hypersensitivity Reaction– Phenytoin, Augmentin, allopurinol

• Microvesicular Steatosis– amiodarone, IV tetracycline, AZT, ddI, stavudine

Acetaminophen Toxicity• 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• NOT in acute EtOH ingestion• NOT in non-alcoholic chronic liver disease

Acetaminophen Toxicity• Day 1:

– Nausea, vomiting, malaise, or asymptomatic

• Day 2 – 3:– Initial symptoms resolve– AST and ALT begin to rise by 36 hours– RUQ pain, tender enlarged liver on exam

• Day 4– AST and ALT peak > 3000– Liver dysfunction: PT, encephalopathy, jaundice– Acute renal failure (ATN)

Acetaminophen ToxicityTreatment

• Activated charcoal if < 4 hours from ingestion– Administer as a single dose 1 mg/kg PO or NG– Does not adversely effect NAC efficacy

• N-Acetylcysteine (NAC)– 140 mg/kg loading dose PO or NG– 70 mg/kg q 4 hours PO or NG X 17 doses

• Continue longer until INR < 2.0 and improved• OK to DC if acetaminophen levels undetectable

and normal AST at 36 hours

Fulminant Hepatic Failure• Definition:

– Rapid development of hepatic dysfunction– Hepatic encephalopathy– No prior history of liver disease

• Most common causes:– Acetaminophen– Unknown– Idiosyncratic drug reaction– Acute HAV or HBV (or HDV or HEV)

Fulminant Hepatic Failure• Close glucose monitoring IV glucose • Avoid sedatives - give PO lactulose• Avoid nephrotoxins and hypovolemia• Vitamin K SQ

– Do not give FFP unless active bleeding, since INR is an important prognostic factor

• GI bleed prophylaxis with PPI• Transfer all patients with FHF who are

candidates to a liver transplant center

5,6741 Liver Transplants in 2003Indications:

• Hepatitis C 29%• Alcoholic Liver Disease 15%• Cirrhosis of unknown etiology 8% • Hepatocellular Carcinoma 7%• Fulminant Hepatic Failure 6%• Primary Sclerosing Cholangitis 5%• Primary Biliary Cirrhosis 4%• Metabolic Liver Disease 4%• Autoimmune Hepatitis 3%• Hepatitis B 3%

Liver Transplantation:Contraindications

• ABSOLUTE– active alcohol or drug abuse– HIV positivity– extrahepatic malignancy– uncontrolled extrahepatic infection– advanced cardiopulmonary disease

• RELATIVE– Age over 65

– poor social support

– poorly controlled mental illness

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)

Obstructive JaundiceCBD 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• Charcot’s 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 CholangitisIndications 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 JaundiceMalignant Causes

• Cancer of the Pancreas

• Cancer of the Bile Ducts (Cholangiocarcinoma)

• Ampullary Tumors

• Portal Lymphadenopathy

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)

Primary Biliary Cirrhosis• Cholestatic liver disease (ALP)

– 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

AIH ALT ANA

ASMA

IgG Portal inflammation

Plasmacytes

Piecemeal necrosis

PBC ALP AMA IgM Bile duct destruction

granulomas

PSC ALP none normal Periductal concentric

fibrosis

Unusual Causes of Jaundice• Ischemic hepatitis

• Congestive hepatopathy

• Wilson’s disease

• AIDS cholangiopathy

• Amanita phalloides (mushrooms)

• Jamaican bush tea

• Infiltrative diseases of the liver– Amyloidosis– Sarcoidosis– Malignancy: lymphoma, metastatic dz

Wilson’s 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

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 PatientHISTORY

• 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

Evaluation of the Jaundiced PatientPHYSICAL 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)

Evaluation of the Jaundiced PatientLAB 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

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

YesYes

Treat

YesYes

Treat