A case on a common disorder

1. Clinical Case:
A Young Male with Jaundice

2. Plan
1. Understanding The Basics
2. Approach to Jaundice
3. Answering the Case Discussion Questions

3. 1. Understanding The Basics

4. 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

5. 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

6. 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

7. • 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

8. • 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 ducts
Initial steps in evaluating the patient with jaundice is to
determine: 1) Whether the hyperbilirubinemia is predominatly
conjugated or unconjugated In nature
2) Whether the biochemical liver tests are abnormal

9. 2. Approach To Jaundice

11. Isolated Elevation of Serum Bilirubin
• Unconjugated hyperbilirubinemia
– Differential diagnosis is limited

12. • 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

13. 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

14. 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

15. 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.

16. • 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

17. 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

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

19. 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

20. 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?

21. 3. Answering Clinical Case
Questions

22. 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)

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

24. 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

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

26. 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

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

28. 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

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

30. • 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).

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

33. • 6. Classify jaundice according to the
mechanisms

34. • 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.

35. • 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?

36. • 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.

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

38. Laboratory Investigations
• Serologic screening for hepatitis antibody:
HCV antibody, HBsAg
• Blood alcohol levels
• Autoimmune hepatitis: ANA, ASMA, AMA, IgG

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

40. 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.

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

42. • Liver Biopsy

43. Thank you! 