JaundiceDaniel eshetu

QUESTION

Describe the abnormal findings in this patient.

Jaundice Definition

Jaundice/ Icterus

• Is a condition characterized by yellow discoloration of the skin, sclera and mucous membranes as a result of wide spread tissue deposition of the pigment metabolite, bilirubin.

• Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia (>1.5mg/dl).

• Jaundice is generally a sign of liver/biliary tract diseases but can also occur in hemolytic disorders as well as many other diseases.

Jaundice

Bilirubin is potentially toxic to tissues and organelles .

Fortunately, there are efficient protective physiologic mechanisms

for its detoxification and disposition.

These include binding to plasma albumin during transport, rapid

uptake, conjugation, and clearance by the liver.

Hence, the harmful effects of unconjugated bilirubin is limited to:• neonates with a high degree of unconjugated hyperbilirubinemia (>20mg/dl) kernicterus; &

• subjects with inherited disorders of bilirubin conjugation.

Jaundice cont’d

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

• A logical evaluation of the patient who is jaundiced requires an understanding of bilirubin production and metabolism.

Production & Metabolism of Bilirubin

• Daily production in healthy adults = 250-300mg (4mg/kg )

Sources:

• 80% from the breakdown of hemoglobin in senescent RBCs. s/t premature destruction of RBCs (i.e. ineffective erythropoiesis).

• 20% from breakdown of hemoproteins (catalase & cytochrome oxidases) in hepatocytes.

• Minimal from non-hemoglobin heme-containing proteins in extrahepatic tissues e.g. myoglobin.

Production/Metabolism of Bilirubin

• breakdown RBC derived HEME , occurs in reticuloendothelial cells, in

the spleen, liver , bone marrow.

• Heme consists of a ring of four pyrroles joined by carbon bridges and

a central iron atom (ferroprotoporphyrin IX).

• Bilirubin is generated by two step, sequential catalytic degradation of

heme mediated by two groups of enzymes:

The enzymes

• Heme oxygenase:

functions predominantly as an integral membrane protein of the smooth endoplasmic reticulum.

initiates the opening of the porphyrin ring of heme by catalyzing the oxidation of the alpha-carbon bridge,

is rate-limiting in bilirubin production,

highly concentrated in RES cells of the spleen, & in the Kupffer cells in the liver.

It is also induced by heme, e.g., in hemolytic states.

• Biliverdin reductase: cytosolic protein (rapidly converts biliverdin to bilirubin).

Heme Biliverdin Bilirubin

Production/metabolism cont’d• Bilirubin formed in RES is insoluble in water at physiologic pH b/c

of tight internal hydrogen bonding.

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

• The conversion of bilirubin IX-alpha to a water-soluble form by disruption of the hydrogen bonds is essential for the elimination by the liver and kidney.

Albumin binding/transport in plasma

To be transported in blood, bilirubin is solubilized by its tight, reversible, non-covalent binding to albumin which:

• keeps bilirubin in solution in plasma & in the vascular space;

• thereby preventing its deposition into extrahepatic tissues

(e.g. brain, sclera).

• minimizing its glomerular filtration.

• transports bilirubin to the sinusoidal surface of the

hepatocyte,

Uptake of bilirubin by hepatocytes• In the liver sinusoids, the albumin-bilirubin complex

dissociates, and the bilirubin is taken up efficiently by the hepatocyte while the albumin remains in the circulation.

• Bilirubin is taken up across the sinusoidal (basolateral) membrane of hepatocytes by a carrier-mediated mechanism;mediated by a liver-specific sinusoidal organic anion transport protein, (OATP1B1, SLC21A6).

This process of bilirubin uptake is impaired in certain disease states:

• Gilbert syndrome: some patients have reduced Bilirubin uptake.

• Drugs, e.g. Rifampin, cholecystographic dyes inhibit uptake.

• In cirrhosis,

a portion of the bilirubin produced in the spleen may bypass the liver via

portosystemic collaterals.

the sinusoidal endothelium, normally fenestrated, may lose the fenestrae

(capillarization), thereby creating a barrier between the plasma & the

hepatocytes.

• As a result, serum unconjugated bilirubin concentrations often increase in cirrhosis.

Uptake and conjugation

• Passage of bilirubin across the hepatocyte sinusoidal surface membrane is bidirectional.

• Once in the cytosol of hepatocyte, unconjugated bilirubin is bound proteins including glutathione-S-transferase superfamily & fatty acid binding proteins which:

• reduce efflux of bilirubin back into the serum &

• direct the bilirubin to endoplasmic reticulum, where it is conjugated

to uridine diphosphate (UDP)–glucuronic acid by the enzyme

bilirubin UDP–glucuronyl transferase (B-UGT).

Organization of hepatocyte membrane

Excretion into bile

• The now hydrophilic bilirubin conjugates diffuse from the endoplasmic reticulum to the canalicular membrane,

• where bilirubin as monoglucuronide(20%) & diglucuronide(80%) are actively transported into canalicular bile by an energy-dependent mechanism involving the multiple drug resistance protein 2 or multispecific organic anion transporter, (MRP2/cMOAT)

• Bile pigment appearing in bile is mostly (> 98 %) conjugated, is water soluble.

Bilirubin uptake/excretion by hepatocyte

Bil

AlB

Enterohepatic circulation

• Conjugated bilirubin in bile is not absorbed across the lipid membrane of

the small intestinal epithelium; in comparison, the unconjugated bilirubin

fraction is partially reabsorbed and undergoes Enterohepatic circulation.

• When the conjugated bilirubin reaches the distal ileum & colon, it is

hydrolyzed to unconjugated bilirubin by bacterial –glucuronidases to a

series of molecules, termed urobilinogens.

Enterohepatic and systemic circulation in adults

• 80–90% urobilinogens of these products are excreted in feces, either unchanged or oxidized to orange derivatives called urobilins.

• The remaining 10–20% of the urobilinogens are passively absorbed, enter the portal venous blood, and are reexcreted by the liver.

• A small fraction (<3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in urine.

Enterohepatic and systemic circulation

In disease states

• In complete biliary obstruction or severe intrahepatic cholestasis (eg,

in the early phase of acute viral hepatitis), feces may take the

appearance of china clay lack of stercobilin.

• Thus, the absence of urobilinogen in stool / urine in a jaundiced

patient indicates complete biliary obstruction.

Urinary urobilinogen excretion may be increased in the following situations:

• Excessive bilirubin production (e.g, in cases of hemolysis or absorption of hematoma)

• Inefficient hepatic clearance of the reabsorbed urobilinogen (e.g, in patients with cirrhosis or at some stages of hepatitis)

• Excessive exposure of bilirubin to intestinal bacteria (e.g, constipation or bacterial overgrowth).

urinary urobilinogen excretion can be reduced or abolished in:

•near-complete biliary obstruction (eg, carcinoma of

the pancreas) or

• severe cholestasis (eg, in early stages of viral

hepatitis).

Alternative pathways of bilirubin elimination

• may be important in certain clinical settings. One such pathway is

oxidation of bilirubin by mixed function oxidases in liver and other organs.

• In conditions associated with elevated conjugated plasma bilirubin

concentrations (e.g, intrahepatic or extrahepatic cholestasis), the kidney is

responsible for 50 to 90% of conjugated bilirubin excretion.

• However, bile remains the main excretion route for unconjugated

hyperbilirubinemia.

Measurement of Serum Bilirubin

• Most clinical chemistry laboratories use the van den Bergh reaction 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.

van den Bergh reaction

• The direct fraction is that which reacts with diazotized sulfanilic acid

in the absence of an accelerator substance such as alcohol.

• The direct fraction approximates the conjugated bilirubin in serum.

• The total serum bilirubin is the amount that reacts after the addition

of alcohol.

• The indirect fraction = the Total - the direct bilirubin

estimate of the unconjugated bilirubin in serum.

Normal serum bilirubin

Using the Van den Bergh rxn

• The normal serum bilirubin concentration = <1mg/dl (17 mol/L)

• direct-reacting bilirubin= 0.3 mg/dl (up to 30%) of the total,

• Total serum bilirubin concentrations are between 0.2 and 0.9mg/dl in

95% of a normal population.

Serum half life of bilirubin normally is 4hrs.

Measurement of bilirubin

• Several new techniques, more accurate but are less

convenient to perform, and are not used routinely but have

added considerably to our understanding of bilirubin

metabolism.

Measurement of Urine Bilirubin

• Unconjugated serum bilirubin is always bound to albumin, is not filtered by the kidney (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 in absence of albuminuria implies the presence of liver disease (conjugated hyperbilirubinemia)

Measurement of Urine Bilirubin

• 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.

BILIRUBIN IN DISEASE STATES

• In normal plasma, 1- 4 % of bilirubin is conjugated.

This relationship may vary in disease states:

• In inherited disorders of bilirubin conjugation, the proportion of conjugated

bilirubin is reduced.

• In biliary obstruction or hepatocellular diseases, both conjugated and

unconjugated bilirubin accumulate in plasma.

• In hemolytic jaundice, total plasma bilirubin increases, but the proportion of

the unconjugated and conjugated fractions remains unchanged.

Approach to the Patient:

The bilirubin present in serum represents a balance between input from

production of bilirubin and hepatic/biliary removal of the pigment.

Hyperbilirubinemia may result from

1. overproduction of bilirubin;

2. impaired uptake, conjugation, or excretion of bilirubin; or

3. regurgitation of unconjugated or conjugated bilirubin from

damaged hepatocytes or bile ducts.

Approach to patient• An increase in unconjugated bilirubin in serum results from either

overproduction, impairment of uptake, or conjugation of bilirubin.

• An increase in conjugated bilirubin is due to decreased excretion into the

bile ductules or backward leakage of the pigment.

Approach to patient• The initial steps in evaluating the patient with jaundice are to

determine :

1. whether the hyperbilirubinemia is predominantly conjugated or unconjugated in nature,

2. whether other biochemical liver tests are abnormal.

The thoughtful interpretation of limited data will allow for a rational evaluation of the patient.

ISOLATED ELEVATION OF SERUM BILIRUBIN1. Unconjugated Hyperbilirubinemia

The D/Dx of an isolated unconjugated hyperbilirubinemia is limited .

• hemolytic process resulting in an overproduction of bilirubin (hemolytic disorders and ineffective erythropoiesis) or

• impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders).

I. Indirect hyperbilirubinemia

A. Hemolytic disorders

1. Inheriteda. Spherocytosis, elliptocytosis, G-6-p- d and pyruvate kinase deficienciesb. Sickle cell anemia

2. Acquireda. Microangiopathic hemolytic anemiasb. Paroxysmal nocturnal hemoglobinuriac. Spur cell anemiad. Immune hemolysis

e. Parasitic infections1. Malaria2. Babesiosis

B. Ineffective erythropoiesis

1. Cobalamin, folate, thalassemia, and severe iron deficiencies

C. Drugs1. Rifampicin, probenecid, ribavirin

D. Inherited conditions

1. Crigler-Najjar types I and II

2. Gilbert's

II. Direct hyperbilirubinemia

A. Inherited conditions

1. Dubin-Johnson syndrome

2. Rotor's syndrome.

ELEVATION OF SERUM BILIRUBIN WITH OTHER LIVER TEST ABNORMALITIES

This group of patients can be divided into:

• those with a primary hepatocellular process &

• those with intra- or extrahepatic cholestasis.

This differentiation is made on the basis of the history and physical examination as well as the pattern of liver test abnormalities.

Hepatocellular Conditions that May Produce Jaundice

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, idiosyncratic (e.g.,

isoniazid)

Environmental toxins• Vinyl chloride

• Jamaica bush tea—pyrrolizidinealkaloids

• Kava Kava

• Wild mushrooms—Amanita phalloides or A. verna

Wilson's disease

Autoimmune hepatitis

Cholestatic Conditions: Intrahepatic

A. . I. Intrahepatic

Viral hepatitis1. Fibrosing cholestatic hepatitis—hepatitis B & C

2 Hepatitis A, Epstein-Barr virus, cytomegalovirus

B. Alcoholic hepatitis

C. Drug toxicity1. Pure cholestasis—anabolic and contraceptive steroids

2. Cholestatic hepatitis—chlorpromazine, erythromycin estolate

3. Chronic cholestasis—chlorpromazine and prochlorperazine

D. Primary biliary cirrhosis

E. Primary sclerosing cholangitis

F. Vanishing bile duct syndrome1. Chronic rejection of liver transplants

2. Sarcoidosis

3. Drugs

G. Inherited

1. Progressive familial intrahepatic cholestasis2. Benign recurrent cholestasis

H. Cholestasis of pregnancy

I. Total parenteral nutrition

J. Nonhepatobiliary sepsis

K. Benign postoperative cholestasis

L. Paraneoplastic syndrome

M. Venoocclusive disease

N. Graft-versus-host disease

O. Infiltrative disease1. TB

2. Lymphoma

3. Amyloid

Cholestatic conditions/Extrahepatic

II. Extrahepatic

A. Malignant

1. Cholangiocarcinoma

2. Pancreatic cancer

3. Gallbladder cancer

4. Ampullary cancer

5. Malignant involvement of the

porta hepatis lymph nodes

B. Benign

1. Choledocholithiasis

2. Postoperative biliary structures

3. Primary sclerosing cholangitis

4. Chronic pancreatitis

5. AIDS cholangiopathy

6. Mirizzi's syndrome

7. Parasitic disease (ascariasis)

history

A complete medical history is the single most important part of the evaluation of the patient with unexplained jaundice.

History of :

• the use of or exposure to any chemical or medication, herbal and

vitamin preparations, or drugs e.g. anabolic steroids.

• parenteral exposures, including transfusions, intravenous and

intranasal drug use, tattoos, & sexual activity.

Other important questions History of:

• recent travel; exposure to people with jaundice; exposure to possibly contaminated foods;

• occupational exposure to hepatotoxins; alcohol consumption; the duration of jaundice;

• the presence of any accompanying symptoms such as:• rash, anorexia, weight loss, abdominal pain,• fever, pruritus, and changes in the urine and stool.• arthralgia and myalgia predating jaundice suggests hepatitis, either viral or

drug-related. • sudden onset of severe RUQ pain and shaking chills

choledocholithiasis/ascending cholangitis.

Physical ExaminationGeneral assessment:

• Includes the patient's nutritional status.

• Temporal and proximal muscle wasting suggests long-standing diseases such as pancreatic cancer or cirrhosis.

• Stigmata of CLD, including spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced alcoholic (Laennec's) cirrhosis and occasionally in other types of cirrhosis.

• An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister Mary Joseph's nodule) suggests an abdominal malignancy.

P/E

• JVP distention a sign of right-sided heart failure hepatic congestion.

• Right pleural effusion, in the absence of clinically apparentascites, may be seen in advanced cirrhosis.

• abdominal examination should focus on the size and consistency of the liver, presence of splenomegaly, and ascites.

Patients with cirrhosis may have an enlarged left lobe of the liver, enlarged spleen and ascites.

P/EA grossly enlarged nodular liver or an obvious abdominal massmalignancy.

An enlarged tender liver could be viral or alcoholic hepatitis; an infiltrative process such as amyloid; an acutely congested liver secondary to right-sided heart failure.

Severe right upper quadrant tenderness with respiratory arrest on inspiration (Murphy's sign) suggests cholecystitis or, occasionally, ascending cholangitis.

Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread.

Laboratory tests• battery of tests that are helpful in the initial evaluation of a patient with

unexplained jaundice include:

• Total and direct serum bilirubin with fractionation, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests.

• Enzyme tests ALT, AST, and ALP are helpful in differentiating between a hepatocellular process and a cholestatic process, a critical step in determining what additional workup is indicated

LAB

• Patients with a hepatocellular process generally have a disproportionate rise in the aminotransferases compared to the ALP.

• Patients with a cholestatic process have a disproportionate rise in the ALP compared to the aminotransferases.

• The bilirubin can be prominently elevated in both hepatocellular & cholestatic conditions &, therefore, is not necessarily helpful in differentiating between the two.

Additional important Lab tests to assess liver function

Serum Albumin:• A low albumin level suggests a chronic process e.g. cirrhosis or cancer.

• A normal albumin level is suggestive of a more acute process e.g.viralhepatitis or choledocholithiasis.

Prothrombin Time(PT):• An elevated PT indicates either vitamin K deficiency due to prolonged

jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction.

• The failure of the PT to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.

Lab.

• The results of the bilirubin, enzyme tests, albumin, and PT tests will usually indicate whether a jaundiced patient has a hepatocellular or a cholestatic disease, as well as some indication of the duration and severity of the disease.

• The causes & evaluation of hepatocellular & cholestatic diseases are quite different.

Radiologic/imaging tests

• Ultrasound, Endoscopic U/S, CT scan, MRCP,ERCP are helpful in diagnosis of causes of obstruction to biliary tree and in some cases in treating the patients.

Summary

Heme(Hemoglobin)Unconjugated bilirubin (spleen) Liver

Conjugated bilirubin Bile Intestine/ kidney feces /urine

Management

• Depends on the cause of Jaundice

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