jaundice and hepatosplenomegaly dr. ravi kant assistant professor department of general medicine

Jaundice and Hepatosplenomegaly

Dr. Ravi Kant

Assistant Professor

Department of General Medicine

Introduction

Jaundice or icterus, is a yellowish discoloration of tissue resulting from the deposition of bilirubin.

Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia and is a sign of either liver disease or, hemolytic disorder.

The degree of serum bilirubin elevation can be estimated by physical examination.

The presence of scleral icterus indicates a serum bilirubin of at least 51 mol/L (3 mg/dL).

The ability to detect scleral icterus is made more difficult if the examining room has fluorescent lighting.

As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is long-standing; the green color is produced by oxidation of bilirubin to biliverdin.

Increased serum bilirubin levels occur when an imbalance exists between bilirubin production and clearance.

Production and Metabolism of BilirubinThe formation of bilirubin occurs in

reticuloendothelial cells, primarily in the spleen and liver.

The first reaction, catalyzed by the microsomal enzyme heme oxygenase, oxidatively cleaves the bridge of the porphyrin group and opens the heme ring.

The end products of this reaction are biliverdin, carbon monoxide, and iron.

The second reaction, catalyzed by the cytosolic enzyme biliverdin reductase, reduces the central methylene bridge of biliverdin and converts it to bilirubin.

Bilirubin formed in the reticuloendothelial cells is virtually insoluble in water. This is due to tight internal hydrogen bonding between the water-soluble moieties of bilirubin.

This configuration blocks solvent access to the polar residues of bilirubin and places the hydrophobic residues on the outside.

To be transported in blood, bilirubin must be solubilized. This is accomplished by its reversible, noncovalent binding to albumin.

Unconjugated bilirubin bound to albumin is transported to the liver.

After entering the hepatocyte, unconjugated bilirubin is bound in the cytosol to a number of proteins including proteins in the glutathione-S-transferase superfamily.

These proteins serve both to reduce efflux of bilirubin back into the serum and to present the bilirubin for conjugation.

In the endoplasmic reticulum, bilirubin is solubilized by conjugation to glucuronic acid, a process that disrupts the internal hydrogen bonds and yields bilirubin monoglucuronide and diglucuronide.

The conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine diphosphate-glucuronosyl transferase (UDPGT).

Measurement of Serum Bilirubin

Direct and indirect bilirubin, conjugated and unconjugated bilirubin, respectively, are based on the original van den Bergh reaction.

This assay, is still used in most clinical chemistry laboratories to determine the serum bilirubin level.

In this assay, bilirubin is exposed to diazotized sulfanilic acid, splitting into two relatively stable dipyrrylmethene azopigments that absorb maximally at 540 nm, allowing for photometric analysis.

The direct fraction is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol.

The direct fraction provides an approximate determination of the conjugated bilirubin in serum.

The total serum bilirubin is the amount that reacts after the addition of alcohol.

The indirect fraction is the difference between the total and the direct bilirubin and provides an estimate of the unconjugated bilirubin in serum.

Total serum bilirubin concentrations are between 3.4 and 15.4 mol/L (0.2 and 0.9 mg/dL) in 95% of a normal population.

Measurement of Urine Bilirubin

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.

Causes of Isolated Hyperbilirubinemia

Indirect Hyperbilirubinemia Direct Hyperbilirubinemia  

 A. Hemolytic disordersB. Ineffective

erythropoiesis C. Drugs D. Inherited

conditions

A. Inherited conditions  

1.Dubin-Johnson syndrome     

2. Rotor's syndrome

Isolated Elevation of Serum BilirubinUnconjugated Hyperbilirubinemia

Hemolytic disorders that cause excessive heme production may be either inherited or acquired.

Inherited disorders include spherocytosis, sickle cell anemia, thalassemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase.

In these conditions, 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 alternative explanation for hyperbilirubinemia.

Gilbert's syndromeIt is also marked by the impaired

conjugation of bilirubin due to reduced bilirubin UDPGT activity to approximately 1/3 of normal.

Gilbert's syndrome have a mild unconjugated hyperbilirubinemia with serum levels almost always <103 mol/L (6 mg/dL).

One molecular defect that has been identified in patients with Gilbert's syndrome is in the TATAA element in the 5' promoter region of the bilirubin UDPGT gene upstream of exon 1.

Conjugated Hyperbilirubinemia

Elevated conjugated hyperbilirubinemia is 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.

The defect in Dubin-Johnson syndrome is mutations in the gene for multiple drug resistance protein 2.

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.

Hepatocellular Conditions that May Produce JaundiceViral hepatitis  Hepatitis A, B, C,

D, and E   Epstein-Barr virus

  Cytomegalovirus

Herpes simplex Alcohol Drug toxicity   Predictable, dose-

dependent   Unpredictable, idiosyncratic

Environmental toxins

  Vinyl chloride   Jamaica bush tea

—pyrrolizidine alkaloids   Kava Kava   Wild mushrooms—Amanita phalloides or A. verna 

Wilson's disease Autoimmune hepatitis

Cholestatic Conditions that May Produce Jaundice

I. Intrahepatic Extra hepaticA. Viral hepatitis    B. Alcoholic

hepatitisC. Drug toxicity    D. Primary biliary

cirrhosis   E. Primary

sclerosing cholangitis   

F. Vanishing bile duct syndrome

A. Malignant     1.

Cholangiocarcinoma     

2. Pancreatic cancer   3. Gallbladder cancerB. Benign      1.

Choledocholithiasis 2. Postoperative

biliary structures      3. Chronic

pancreatitis

Spleen Situated behind 9th, 10th and 11th ribs with its

long axis along the line of 10th rib. It is separated from 9th, 10th, 11th ribs by the

diaphragm. Newer method of percussion of spleen Nixon’s method

The patient is placed on the right side so that the spleen lies above the colon and stomach.

Percussion beings at the lower level of pulmonary resonance in the posterior axillary line toward the lower mid anterior costal margin.

The upper border of dullness is normally 6-8 cm above the costal margin.

Dulness grater than 8cm in an adults is presumed to indicate splenic enlargement.

Castell's method

When patient supine, percussion in the lowest intercostal space in the anterior axillary produce a resonant note if the spleen is inspiration.

A dully percussion note on full inspiration suggests splenomegly.

Hepatosplenomegaly

Causes

A. Infections Malaria Kala – azar Infective

heapatitis

B. Hematological disoders

Anemia CML

Congestive StatesCongestive cardiac

failureCongestive

pericarditis

Storage disordersGaucher’s diseasesAmyloidosis

Causes of Hepatomegaly

infective CholangitisAmoebiasisMalaria, kala-azarActinomycosis

histoplasmosisEchinococcosis

Congestivecardiomyopathy

Digestive and Infiltrative

LymphomasMultiple myeloma

Storage DisordersNiemann- Pick diseasesGaucher’s diseasesAmyloidosis

NeoplasiaToxinsAlcohol, arsenic

Causes of Splenomegaly

Mild(up to 5cm)Congestive cardiac

failureAcute Malaria LeptospirosisModerate Viral hepatitis CirrhosisSplenic abscessPolycythaemia

Massive(>8cm)CMLGaucher’s diseasesThalassaemia

majorKala- azar LymphomaCongenital syphilisNiemann- Pick

diseaseSarcoidosis

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