Approach to a pt with Jaundice

Presented by Dr.Mitun debonath Intern doctor Medicine unit-1 RMCH

 Jaundice, or icterus, is a yellowish discoloration of tissue resulting from the deposition of bilirubin.  The presence of scleral icterus indicates a serum bilirubin of at least 51 mol/L (3.0 mg/dL). If the examiner suspects scleral icterus, a second place to examine is underneath the tongue.  As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is

 The differential diagnosis for yellowing of the skin is  Carotenoderma occurs in healthy individuals who ingest excessive amounts of vegetables and fruits that contain carotene, such as carrots, leafy vegetables, squash, peaches, and oranges.  Unlike jaundice, where the yellow coloration of the skin is uniformly distributed over the body, in carotenoderma the pigment is

 Carotenoderma can be distinguished from jaundice by the sparing of the sclerae.  Quinacrine  Excessive exposure to phenols.  Another sensitive indicator of increased serum bilirubin is darkening of the urine, which is due to the renal excretion of conjugated bilirubin.  Patients often describe their urine as tea or cola colored.  Bilirubinuria indicates an elevation of the

Production and Metabolism of Bilirubin

 Bilirubin is a breakdown product of heme .  About 7080% of the 250300 mg of bilirubin produced each day is derived from the breakdown of hemoglobin in senescent red blood cells. The remainder comes from prematurely destroyed erythroid cells in bone marrow and from the turnover of hemoproteins such as myoglobin and cytochromes found in tissues throughout the body.

 The formation of bilirubin occurs in reticuloendothelial cells, primarily in the spleen and liver. Microsomal enzyme heme oxygenase breaks heme molecule in to biliverdin, cytosolic enzyme biliverdin reductase converts it to bilirubin.  Bilirubin formed in the reticuloendothelial cells is virtually insoluble in water.  To be transported in blood, bilirubin must be solubilized.  This is accomplished by binding to albumin. Unconjugated bilirubin bound to

 After entering the hepatocyte bilirubin is solubilized by conjugation to glucuronic acid, a process that yields bilirubin monoglucuronide and diglucuronide.  The conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine diphosphate-glucuronosyl transferase (UDPGT).  The now hydrophilic bilirubin conjugates diffuse from the endoplasmic reticulum to the canalicular membrane, where bilirubin monoglucuronide and diglucuronide are actively transported into canalicular bile.

 The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the proximal small bowel.  Conjugated bilirubin is not taken up by the intestinal mucosa. When the conjugated bilirubin reaches the distal ileum and colon, it is hydrolyzed to unconjugated bilirubin by bacterial -glucuronidases.  The unconjugated bilirubin is reduced by normal gut bacteria to form a group of colorless tetrapyrroles called urobilinogens. About 8090% of these products are excreted in feces, either

 The remaining 1020% of the urobilinogens are passively absorbed, enter the portal venous blood, and are reexcreted by the liver. A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in urine.  Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not found in the urine.  Conjugated bilirubin is filtered at the glomerulus and the majority is reabsorbed by the proximal tubules; a small fraction is excreted in the urine.

 Any bilirubin found in the urine is conjugated bilirubin. The presence of bilirubinuria implies the presence of liver disease.  A urine dipstick test (Ictotest) gives the same information as fractionation of the serum bilirubin. This test is very accurate.  A false-negative test is possible in patients with prolonged cholestasis due to the predominance of conjugated bilirubin covalently bound to albumin.

Hyperbilirubinemia may result from  Overproduction of bilirubin  Impaired uptake, conjugation, or excretion of bilirubin  Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts.

Pre-hepatic jaundice
This is caused either by haemolysis or by congenital hyperbilirubinaemia, and is characterised by an isolated raised bilirubin level. In haemolysis, destruction of red blood cells or their precursors in the marrow causes increased bilirubin production. Jaundice due to haemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma. This does not apply to the newborn, who have a reduced

 The most common form of non-haemolytic hyperbilirubinaemia is Gilbert's syndrome, an inherited disorder of bilirubin metabolism. Gilbert's syndrome is also marked by the impaired conjugation of bilirubin due to reduced bilirubin UDPGT activity. Other inherited disorders of bilirubin metabolism also exist but they are very rare.  Patients with Gilbert's syndrome have a mild unconjugated hyperbilirubinemia with serum levels almost always <103 mol/L (6 mg/dL).  The serum levels may fluctuate, and jaundice is often identified only during periods of fasting. The reported incidence is 37% of the population with males predominating over

 Crigler-Najjar type I is an exceptionally rare condition found in neonates frequently leading to death in infancy or childhood. These patients have a complete absence of bilirubin UDPGT activity,  Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels that range from 103428 mol/L (625 mg/dL). In these patients, mutations in the bilirubin UDPGT gene cause reduced but not completely absent activity of the enzyme. Bilirubin UDPGT activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these

 In haemolytic hyperbilirubinaemia, the serum bilirubin rarely exceeds 86 mol/L (5 mg/dL). Higher levels may occur when there is coexistent renal or hepatocellular dysfunction or in acute hemolysis such as a sickle cell crisis.  In evaluating jaundice in patients with chronic hemolysis, it is important to remember the high incidence of pigmented (calcium bilirubinate) gallstones found in these patients, which increases the likelihood of choledocholithiasis as an

Hepatocellular jaundice
 Hepatocellular jaundice results from parenchymal liver disease. Bilirubin transport across the hepatocytes may be impaired at any point between uptake of unconjugated bilirubin into the cells and transport of conjugated bilirubin into the canaliculi. In addition, swelling of cells and oedema resulting from the disease itself may cause obstruction of the biliary canaliculi. In hepatocellular jaundice the concentrations of both unconjugated

Hepatocellular jaundice
 Hepatocellular jaundice can be due to acute or chronic liver. Characteristically, jaundice due to parenchymal liver disease is associated with increases in transaminases (AST, ALT), but increases in other LFTs, including cholestatic enzymes (GGT, ALP) may occur, and suggest specific aetiologies

Obstructive jaundice
Cholestatic jaundice may be caused by:  failure of hepatocytes to initiate bile flow  obstruction of bile flow in the bile ducts or portal tracts  obstruction of bile flow in the extrahepatic bile ducts between the porta hepatis and the papilla of Vater. In the absence of treatment, cholestatic jaundice tends to become progressively more severe because conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood, and also

Obstruction of the bile duct drainage due to blockage of the extrahepatic biliary tree is characteristically associated with pale stools and dark urine. Pruritus may be a dominant feature, and can be accompanied by skin excoriations. Peripheral stigmata of chronic liver disease are absent. Cholestatic jaundice is characterised by a relatively greater elevation of ALP and GGT than the aminotransferases.

History of a Jaundice pt
 Prodrome of anorexia, nausea, vomiting, malaise, aversion to smoking. exposure to people with jaundice, exposure to possibly contaminated foods & water suggest- Acute Hepatitis (A,E)  A healthy-appearing young woman with multiple spider nevi , cutaneous striae, acne, hirsutism, Amenorrhea and postpartum exacerbations with extrahepatic features include arthritis, Sjgren syndrome, thyroiditis, nephritis, ulcerative colitis, and Coombs-positive hemolytic anemia suggest-

 Middle-aged women with excessive daytime somnolence, pruritus, Xanthomatous lesions, steatorrhea, and cognitive dysfunction suggest - Primary Biliary Cirrhosis.  Arthropathy, skin pigmentation (combination of slate-gray due to iron and brown due to melanin, sometimes resulting in bronze color), heart failure or conduction defects, diabetes mellitus, and impotence in men suggest Hemochromatosis  Any child or young adult with jaundice,

 Right upper quadrant pain and tenderness, ascites.H/O myeloproliferative disease, protein C or S or antithrombin deficiency, hyperprothrombinemia , antiphospholipid antibodies, paroxysmal nocturnal hemoglobinuria, Behet syndrome, blunt abdominal trauma, use of oral contraceptives, and pregnancy suggest- Hepatic Vein Obstruction (BuddChiari Syndrome)  Men aged 2050 years, h/o ulcerative colitis,progressive jaundice, itching,

 Lung disease (emphysema) suggest Alpha1-antitrypsin  Drug/herbal remedy history suggest- Druginduced liver disease  Malabsorption suggest- Coeliac disease  Metabolic syndrome (central obesity, diabetes, hypertension) suggest- Nonalcoholic fatty liver disease (NAFLD)  Injection drug use, blood transfusion suggest- hepatitis B, hepatitis C

Examination of a patient with jaundice

 Look for signs of chronic liver disease:
 hands - finger clubbing, palmar erythema, leukonychia  upper trunk, head, neck and arms - spider naevi  gynaecomastia in males.

 Look for signs of liver failure:

 flapping tremor of outstretched hands  smell breath for fetor hepaticus  confusion, diminished mental state.

 Look for pallor - haemolytic anaemia.  Look for signs of weight loss - malignancy with liver metastases.

 Smell breath for alcohol.  Examine abdomen for hepatomegaly, splenomegaly, ascites (shifting dullness) and periumbilical caput medusae.  Look for:
 evidence of drug misuse - needle track marks  tattoos  body piercing.

Examination of a patient with jaundice

 Look for scratch marks of itching (obstructive jaundice).  Examine ankles and sacrum for oedema (hypoalbuminaemia).

Jaundice with Lymphadenopathy

     
Lymphoma Leukemia(ALL) IM DT Disseminated malignancy Viral Hepatitis (Cervical rarely epitrochlear)

Jaundice with hepatomegaly

Chronic parenchymal liver disease  Alcoholic liver disease  Autoimmune hepatitis  Viral hepatitis  Primary biliary cirrhosis  Haemochromatosis Malignancy  Primary hepatocellular cancer  Secondary metastatic cancer

Jaundice with hepatomegaly

Right heart failure Haematological disorders  Lymphoma  Leukaemia Rarities  Budd-Chiari syndrome

Jaundice with fever & rash

 Malaria  Leptospira  Dengue  Viral hepatitis  Septicemia  Rickettial diseases  Yellow fever

Jaundice with renal impairment

 Haemolytic uremic syndrome  Hepatorenal syndrome  Leptospirosis  Hepatitis B with Nephrotic syndrome  Alchoholic cirrhosis with IgA nephropathy  Polycystic Kidney diseases with hepatic fibrosis  Stanffes syndome- Renal cell carcinoma with non metastatic hepatic dysfunction

 If the gallbladder is palpable, the jaundice is unlikely to be caused by biliary obstruction due to gallstones, probably because a chronically inflamed stonecontaining gallbladder cannot readily dilate. This is Courvoisier's Law, and suggests that jaundice is due to a malignant biliary obstruction (e.g. pancreatic cancer).  Cholangitis is characterised by 'Charcot's triad' of jaundice, right upper quadrant

The initial steps in evaluating the patient with jaundice are to determine whether the hyperbilirubinemia is predominantly conjugated or unconjugated in nature, and  whether other biochemical liver tests are abnormal.

Isolated Elevation of Serum Bilirubin  Unconjugated Hyperbilirubinemia Hemolytic disorders and ineffective erythropoiesis  Impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders).  Conjugated Hyperbilirubinemia - found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor's syndrome . Patients with both conditions present with asymptomatic jaundice, typically in the second generation of life. These patients have altered excretion of bilirubin into the bile ducts. Rotor's syndrome seems to be a problem with the hepatic storage of bilirubin. Differentiating

Indirect hyperbilirubinemia causes

A. Hemolytic disorders 1. Inherited a. Spherocytosis, elliptocytosis ,Glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies b. Sickle cell anemia 2. Acquired a. Microangiopathic hemolytic anemias b. Paroxysmal nocturnal hemoglobinuria c. Immune hemolysis B. Ineffective erythropoiesis 1. Cobalamin, folate, thalassemia, and severe iron deficiencies C. Drugs 1. Rifampicin, probenecid, ribavirin D. Inherited conditions 1. Crigler-Najjar types I and II 2. Gilbert's syndrome

Direct hyperbilirubinemia
A. Inherited conditions 1. Dubin-Johnson syndrome 2. Rotor's syndrome Hyperbilirubinemia with other abnormal biochemical liver tests are Hepatocellular Conditions  Cholestatic Conditions

Hepatocellular Conditions
 Viral hepatitis Hepatitis A, B, C, D, and E, Epstein-Barr virus, Cytomegalovirus,Herpes simplex  Alcohol  Drug toxicity Predictable, dose-dependent, e.g., acetaminophen, Unpredictable, idosyncratic, e.g., isoniazid  Environmental toxins Vinyl chloride, Jamaica bush tea pyrrolizidine alkaloids, Kava Kava, Wild mushroomsAmanita phalloides or A. verna  Wilson's disease  Autoimmune hepatitis

Causes of cholestatic jaundice

Intrahepatic  Primary biliary cirrhosis  Primary sclerosing cholangitis  Alcohol  Drugs  Cystic fibrosis  Severe bacterial infections  Hepatic infiltrations (lymphoma, granuloma, amyloid, metastases)  Pregnancy  Inherited cholestatic liver disease, e.g. benign recurrent intrahepatic cholestasis  Chronic right heart failure

Causes of cholestatic jaundice Extrahepatic

 Carcinoma  Ampullary  Pancreatic  Bile duct (cholangiocarcinoma)  Liver metastases

 Choledocholithiasis  Parasitic infection  Traumatic biliary strictures  Chronic pancreatitis