Clinical Case on Jaundice

Clinical Case:A Young Male with Jaundice

Plan

1. Understanding The Basics2. Approach to Jaundice3. Answering the Case Discussion Questions

1. Understanding The Basics

What is it?

• Jaundice or icterus is a yellowish discoloration of tissue resulting from the deposition of billirubin– Occur only in the presence of serum

hyperbilirubinemia– Sign of either liver disease or less often, hemolytic

disorder– Indication of serum bilirubin > 3mg/dl– Florescent light does not detect icterus– Scleral icterus under the tongue

Our differential

• Yellow skin differential is limited– Jaundice– Carotenoderma– Quinacrine– Phenols– Quinacrine causes a yellow discoloration of the skin in 4-

37% of patients treated with it. It can cause scleral to sclera• Darkening of urine is a sensitive indicator– Tea or cola-colored – renal exretion of conjugated billirubin

Production and Metabolism of BIlirubin

• Tetrapyrrole pigment– Breakdown product of heme (ferroprotoporphyrin

IX)– 70-80% of the 250-300 mg of bilirubin produced

each day is derived from the breakdown of hemoglobin in senescent red blood cells.

– The remainder comes from prematuerly destroyed erythroid cells in bone marrow and from turnover of hemoproteins such as myoglobin and cytochromes found in tissues throughout the body

• Billirubin occurs in reticuloendothelial cells, primarily in spleen and liver– Catalyzed by the microsomal enzymes heme

oxygenase • Oxidatively cleaves the alpha bridge of prophyrin group

– Opens heme ring

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

– Second reaction, catalyzed by the cytosolic enzyme biliverdin reductase, reduces the central methylene bridge of biliverdin and converts it to bilirubin

• Bilirubin present in serum a balance between input from production of bilirubin and hepatic biliary removal of the pigment– Hyperbilirubinemia result from

• Overproduction of bilirubin• Impaired uptake, conjugation, or excretion of bilirubin• Regurgitation of unconjugated or conjugated bilirubin from

damaged hepatocyte or bile ductsInitial steps in evaluating the patient with jaundice is to determine: 1) Whether the hyperbilirubinemia is predominatly conjugated or unconjugated In nature2) Whether the biochemical liver tests are abnormal

2. Approach To Jaundice

Isolated Elevation of Serum Bilirubin

• Unconjugated hyperbilirubinemia– Differential diagnosis is limited

• Inherited disorders– Include spherocytosis– Sickle cellc anemia– Thalasemia– Deficiency of red cell enzymes such as pyruvate kinase and glucose-6

phosphate deyhydrogenase• Acquired

– microangiopathic hemolytic anemia– Paroxysmal nocturnal hemoglobinuria– Spur cell anemia– Immune hemolysis and parasitic infections including malaria and

babesiosis– Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies

Conjugated Hyperbilirubinemia

• Elevated conjugated hyperbilirubinemia is found in two rare inherited conditions:– Dublin-Johnson syndrome– Rotor’s syndrome• Both present with asymptomatic jaundice, typically

second generation of life– Dublin johnson defect is mutiation for multiple drug

resistance protein 2– Altered bilirubin excretion in bile duct– Rotor syndrome to be a problem of hepatic storage of

bilirubin

History• Use of or exposure to any chemical or medication• Possible parenteral exposures:

– Transfusions, IV or intranasal drug use, tattoos, sexual activity• Contaminated foods• Occupational exposure to hepatotoxins• Alcohol consumptions• Duration of jaundice• Accompanying symptomps: pain, fever, pruritus, and changes in urine

or stool.• Hx of arthalgia and myalgias predating jaundice suggests hepititis,

either viral or drug-related.• Sudden onset with severe right quadrant pain and shaking cells

– Choledocholithiasis and ascending colangitis

Physical Examination

• General assessment should include assessment to the patient’s nutritional status– Temporal and proximal muscle wastings– Suggest long standing diseases such as pancreatic

cancer or cirrhosis– Stigamata of chronic liver disease: Spider nevi, palmar

erythema, gynecomastia, caput medusae, Duputyren’s contractures, parotid enlargement. And testicular atrophy are commonly seen in advanced alcoholic (Laennec’s) cirrhosis and nodule (Sister mary joseph’s nodule) suggest an abdominal malignancy.

• Abdominal examination should focus on the size and consistency of the liver, whether spleen is palpable and hence enlarged, and whether there is ascites present.

• Cirrhosis enlarged left lobe of liver– Felt below the xiphoid and enlarged spleen– Grossly enlarged nodular liver or an obvious abdominal mass suggests

malignancy• Enlarged tender liver could be viral or alcoholic hepatitis

– Infiltrative process such as amyloid– Congested liver secondary to right sided heart failure– Severe upper quadrant tenderness with respiratory arrest on inspiration

(murphy’s sign)• Suggests cholecystitis or ascending cholangitis• Cirrhosis or malignancy with peritoneal spread

LABS

• Total and direct serum bilirubin with fractionation, aminotransferases, alkaline phosphatases, albumin and prothrombin time tests.– Enzyme tests: ALT, AST, and ALP are helpful in

differentiating hepatocellular and cholestatic process– Albumin level and prothrombin time

• Low albumin chronic process such as cirrhosis or cancer• Normal albumin acute process such as viral hepatitis or

choledocholithiasis

Hepatocellular Conditions

• Can cause jaundice include viral hepatitis, drug or enviromental toxicity alcohol and end stage cirrhosis from any cause.

Cholestatic Conditions

• Liver tests suggests a cholestatic disorder– Next step is to determine wether it is intra- or

extrahepatic cholestasis• Intrahepatic from extrahepatic cholestasis may be

difficult• Hx, px and labs are often not helpful

– Ultrasound • Does not expose the patient to ionizing radiation• Can detect dilation of intra and extra hepatic billiary

tree with high degree of sensitivity and specifity

SIMPLY!

• Initial step– Obtain appropriate blood tests to determine if

the patient has an isolated elevation of serum bilirubin

– Is the bilirubin elevation due to an increased unconjugated or conjugated fraction?• Hyperbilirubinemia is acommpanied by other liver test

abnormaities

– Is it hepatocellular or cholestatic?• If cholestatic is it intra or extrahepatic?

3. Answering Clinical Case Questions

Case Scenario

• Abdullah is 21 y.o. male presented to the E.R after he noticed his “eyes looked yellow” for the past 1 month. He has no other symptoms but for the past 2 months he noticed easy fatigability mild pruritus. He also noted that his urine has become dark. There was no history of jaundice before and he did not report any history of fever, headache or confusion. He has not noted any abdominal swelling, pain or weight loss.

• On physical examination, he is afebrile but deeply jaundiced. Blood pressure = 130/68 mm Hg, pulse = 88 bpm and respiratory rate = 16 bpm. Abdominal exam is notable for enlarged liver 15 cm but no shifting dullness, bulging flanks, or “fluid wave”. There was no splenomegaly. Thyroid, skin, breast, cardiovascular, chest and neurological exams were unremarkable. There was mild lower limb edema.

• Laboratory investigations: Complete Blood Count (CBC) WBC 3800, hemoglobin 112 g/L, platelets 210,000. PTT normal but INR 1.6 (0.9-1.2). Hepatic profile is notable for: AST = 220 U/L (10-40) ALT = 305 U/L (10-40) , alkaline phosphatase = 125 U/L [40-100 U/L); albumin = 30 g/L [35-50 g/L]; total bilirubin = 130 umol/L [5-20 umol/L]. Direct bilirubin 80 umo/L (<5 umol/L)

• 1. What are the active problems in this patient?

Active Problems

• Jaundice• Fatigue• Pruritis• Hepatomegaly: 15 cm (normal 6-12)• Mild lower limb edema• Low hemoglobin, Albumin• High INR, alkaline phosphatase, ALT, AST, total

and direct bilirubin

• 2. What other information in the history and physical examination you need to know to reach the correct diagnosis?

Information

• Previous Hepatitis• Hepatitis factors: *A-E-F: Fecal oral B-C-D-G: Parenteral (IV)• Alcohol• Blood transfusions• Multiple sexual partners• Recent travel• Medications• Herbal medications

• Stigmata of chronic liver disease• Abdominal masses• Tattoos

• 3. Do you think he has “chronic liver disease?” What are the clinical stigmata of chronic liver disease?

Stigmata of Chronic Liver Disease

• Clubbing • Palmar erythema• Pruritis• Spider nevi (angiomata)• Testicular atrophy - Gynaecomastia - Feminising hair distribution• Bruising (coagulopathy)• Drowsiness - Hyperventilation - Flapping tremor – Fetor Hepaticus

(Encephalopathy)• Jaundice (excretory dysfunction)• Ascites, Caput Medusae (portal hypertension and hypoalbuminaemia)• Peripheral Edema (hypoalbuminaemia)• Leukonychia (hypoalbuminaemia)• Dupuytren's contracture • Hepatomegaly

• 4. Do you think this patient has unconjugated or conjugated hyperbilirubinemia and why?

• Conjugated hyperbilirubinemia

• Direct Bilirubin = Conjugated Bilirubin

• Conjugated bilirubin means the liver is conjugating normally, but is not able to excrete (Obstruction within liver or in bile duct).

• 5. Explain in “drawing” bilirubin metabolism pathway.

• 6. Classify jaundice according to the mechanisms

• Pre-hepatic/ hemolytic: the pathology is occurring prior to the liver.• E.g. Sickle cell anemia, Thalassemia, G6PD deficiency

• Hepatic/ hepatocellular: the pathology is located within the liver.• E.g. Acute or Chronic Hepatitis, alcoholic liver disease, hepatotoxicity,

cirrhosis, drug induced hepatitis

• Post-Hepatic/ cholestatic: the pathology is located after the conjugation of bilirubin in the liver.

• E.g. gallstones, pancreatic cancer, a group of parasites known as liver flukes can live in the common bile duct, causing obstructive jaundice, stricture of the common bile duct, biliary atresia, cholangiocarcinoma, and pancreatitis.

• 7/8. What are the most important enzymes produced by the liver and commonly tested by the lab? How would you approach/classify the abnormalities in liver enzymes?

• Alanine Transaminase (ALT): elevation indicates hepatitis, liver injury

• Aspartate transaminase (AST): elevation indicates acute liver damage.

• Alkaline Phosphatase (ALP): elevation indicates bile duct obstruction, intrahepatic cholestasis, or infiltrative diseases of the liver.

• Gamma Glutamyl Transpeptidase (GGT): elevation indicates chronic alcohol toxicity.

• 9. What is your next step in evaluating the patient’s jaundice?

Laboratory Investigations

• Serologic screening for hepatitis antibody: HCV antibody, HBsAg

• Blood alcohol levels• Autoimmune hepatitis: ANA, ASMA, AMA, IgG

• 10. What imaging modalities can be used? What are the benefits of each?

Imaging– Abdominal US: Safe/Noninvasive, visualizes gallbladder, bile ducts, cystic

lesions, and detects parenchymal liver disease - cirrhosis/infiltration - and signs of portal hypertension.

– Abdominal CT: Better resolution, visualizes the entire bile duct, is better for evaluating suspected malignancies, and permits guided needle biopsies.

– Abdominal MRI: No radiation risk (pregnancy); Permits multiple contrast agents and scanning techniques, permits guided needle biopsies, and with special contrast agents, can evaluate bile and pancreatic ducts.

– Endoscopic retrograde cholangiopancreatography (ERCP): Allows treatment of obstruction using sphincterotomy, stone extraction, stent placement, or balloon-dilation of strictures. Permits biopsies under direct visualization and provides excellent visualization of bile ducts.

– Percutaneous transhepatic cholangiography (PTHC): Same as ERCP, but more successful. Also more invasive and uses radiation.

• 11. What other important investigations you need to order to reach the final diagnosis?

• Liver Biopsy

Thank you!