This document provides an overview of approaches to jaundice in hospitalized patients. It discusses various causes of jaundice including extrahepatic and intrahepatic disease processes, drug-induced liver injury, ischemic hepatitis, granulomatous hepatitis, hepatic amyloidosis, hepatic sarcoidosis, postoperative jaundice, sepsis-induced cholestasis, and intrahepatic cholestasis of pregnancy. For each condition, it describes the pathogenesis, clinical manifestations, diagnostic evaluation, and management considerations.

1. Approach to Jaundice in
hospitalized patient
PRESENTER:DR.ABHINAV KUMAR

2. OUTLINE
• Bilirubin Metabolism
• Extra-hepatic Disease Processes
• Drug Induced liver Injury
• Ischemic Hepatitis
• Granulomatous Hepatitis
• Hepatic Amyloidosis
• Hepatic sarcoidosis
• Post Operative Jaundice
• Sepsis Induced cholestasis
• Intrahepatic cholestasis of Pregnancy
• Post-bone marrow transplant syndromes

5. Conjugation
• very poorly soluble in water at physiologic pH
• fully hydrogen-bonded structure of bilirubin is designated bilirubin IX-alpha-
ZZ.
• Water-insoluble unconjugated bilirubin  toxic effects of bilirubin.
• internal hydrogen bonding is critical in producing bilirubin toxicity and also
preventing its elimination.
• disruption of the hydrogen bonds, is essential for the elimination by the
liver and kidney.
• glucuronic acid conjugation of the propionic acid side chains of bilirubin
• Bilirubin is primarily excreted in normal human bile as the diglucuronide;

6. Measurement of serum bilirubin
• Reaction of bilirubin with diazo reagents causes breakdown of the
tetrapyrrole to two azodipyrroles (the van den Bergh reaction)
• Because the central carbon bridge of bilirubin is buried within the
molecule by hydrogen bonds, unconjugated bilirubin reacts slowly
with the diazo reagent.
• Conjugated bilirubin, which lacks hydrogen bonds, reacts rapidly even
in the absence of accelerators ("direct" van den Bergh reaction)
• On disruption of hydrogen bonds by addition of "accelerators" such
as methanol or caffeine, the reaction is completed rapidly (total
bilirubin).

7. METABOLISM OF BILIRUBIN

8. Albumin binding of bilirubin in
plasma
• Albumin binding keeps bilirubin in the vascular space
• Transports bilirubin to the sinusoidal surface of the hepatocyte,
where the pigment dissociates from albumin and enters the
hepatocyte.
• Plasma bilirubin content increases after albumin infusion because of
transfer of the pigment from tissue stores to the intravascular space.

9. Albumin binding of bilirubin in
plasma
• Several other ligands bind to albumin at the same site as bilirubin,
• sulfonamides
• warfarin
• Anti-inflammatory drugs
• cholecystographic contrast media
• Agents can displace bilirubin from albumin,
• precipitating bilirubin encephalopathy in newborns without an
alteration in the total serum bilirubin concentration

10. Albumin binding of bilirubin in
plasma
• Albumin binding of bilirubin is usually reversible
• Irreversible binding can occur in the presence of prolonged
conjugated hyperbilirubinemia (eg, during biliary obstruction).
• Delta-bilirubin is not cleared  prolonged hyperbilirubinemia after
endoscopic or surgical relief of biliary obstruction.
• delta-bilirubin gives a "direct" diazo reaction, this may give a false
impression of a persistent blockage of the bile ducts
• Delta-bilirubin  absence of bilirubin excretion in the urine despite
the apparent presence of direct hyperbilirubinemia

11. Uptake and storage of bilirubin by hepatocytes

12. DISEASES IMPAIRING UPTAKE
• Bilirubin uptake is reduced in some, but not all, patients with Gilbert
syndrome and is inhibited by certain drugs (eg, rifampin flavaspidic
acid, and cholecystographic dyes).
• Re-uptake of conjugated and unconjugated bilirubin  Rotor
syndrome  mutations or deletion of both SLCO1B1 and SLCO1B3,
loss of function of both OATP1B1 and OATP1B3.
• Cirrhosis, a portion of the bilirubin produced in the spleen may
bypass the liver via portosystemic collaterals.
• sinusoidal endothelium, which is normally fenestrated, may lose the
fenestrae (capillarization), thereby creating a barrier between the
plasma and the hepatocytes. Increased serum unconjugated
bilirubin.

13. Conjugation of bilirubin

14. IMPAIRED Conjugation of bilirubin
• Inhibitory factor for hepatic UGT1A1 is secreted in the milk of some
mothers breast milk jaundice
• inhibitory factor present in maternal plasma may be transplacentally
transferred to the fetus Lucey Driscoll syndrome
• UGT1A1 deficiency also may be seen in neonates, chronic hepatitis
• Inherited disorders (Gilbert syndrome and Crigler-Najjar syndrome I
and II)

15. Excretion of conjugated bilirubin
• four types of canalicular transporters, the multispecific organic anion
transporter, also termed multidrug resistance protein 2 or ATP-
binding cassette (ABC).
• a portion of the conjugated bilirubin is secreted back into the
sinusoidal blood via the ATP hydrolysis-coupled pump ABCC3.
• Reuptake of the conjugated bilirubin by hepatocytes downstream to
the sinusoidal blood flow is mediated by the sinusoidal surface
organic anion transporters OATP1B1 and OATP1B3.
• The recruitment of additional hepatocytes increases the hepatic
excretory capacity for conjugated bilirubin, which is rate limiting in
bilirubin

16. IMPAIRED Excretion of conjugated
bilirubin
• Enhanced bile flow (by infusion of bile salts)
or phenobarbital treatment increases the maximal bilirubin excretory
capacity.
• alcoholic or viral hepatitis,
• cholestasis of pregnancy
• inherited disorders (Dubin-Johnson syndrome, Rotor syndrome,
benign recurrent intrahepatic cholestasis)
• Drugs (alkylated steroids, chlorpromazine)

17. BILIRUBIN IN DISEASE STATES
Dubin-Johnson
syndrome
Rotor
syndrome

18. BILIRUBIN IN DISEASE STATES
• 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

19. Extra-hepatic Disease Processes
• The most common cause  choledocholithiasis
Biliary obstruction can also be caused by strictures related to
• cholangiocarcinoma
• pancreatic cancer
• metastatic disease to adjacent lymph nodes
• postoperative strictures (after cholecystectomy or liver
transplantation)
• Mirizzi syndrome
• Primary sclerosing cholangitis
• Large pancreatic cysts or pseudocysts, especially at the head of the
pancreas

20. Intrahepatic Disease Processes
• Drug-induced liver injury

24. ISCHEMIC HEPATITIS
• Ischemic hepatitis refers to diffuse hepatic injury resulting from acute
hypoperfusion
• Ischemic hepatitis accounts for 1 to 2.5 percent of patients admitted
to an intensive care unit

25. Clinical manifestations
• Any cause of shock or hemodynamic instability can cause ischemic
injury to the liver
• Focal interruption of the hepatic blood supply
– hepatic sickle cell crisis
– hepatic artery thrombosis in patients who have undergone liver
transplantation
– Preexisting portal vein thrombosis
• Ischemic hepatitissevere respiratory failure, systemic hypoxemia,
obstructive sleep apnea, and acute lower limb ischemia

26. PATHOGENESIS
• Imbalance between hepatic oxygen supply and demand
Regulation of blood flow
• Hepatic oxygen delivery is related to the oxygen content of blood
perfusing the liver and total hepatic blood flow
• Once oxygen delivery is decreased  Autoregulation of blood flow
appears to play an important role
• Hepatic arterial flow is regulated closely to maintain relatively
constant total hepatic blood flow.
• By contrast, portal venous flow lacks autoregulatory control

27. Portal flow declines
smooth muscle cells around hepatic arterioles relax
increased arteriolar flow
Increased adenosine within connective tissue that surrounds hepatic
arterioles
concentration of adenosine  degree to which it is "washed out" by
sinusoidal blood flow
• Zone 3 of the hepatic acinus is particularly vulnerable to a circulatory
insult

28. Blood flow under systemic stress
• Sepsis  Cardiac output may not increase sufficiently to supply
demands of critical organs such as the brain.
• Compensatory decrease in peripheral and splanchnic blood flow
• Decrease in hepatic blood flow may exceed the capacity of the liver
to increase oxygen extraction
Hepatocellular hypoxia, especially in zone 3

29. Reperfusion and other mechanism of injury
Reperfusion injury
Histologically apparent damage.
Ischemic hepatocytes  oxygen  Reactive oxygen species
Leading to cell injury via lipid peroxidation
Kupffer cells react to ischemia
cytokines, including TNF-alpha
Recruitment and activation of PMN

30. Ischemia promotes
• Cytosolic xanthine dehydrogenase Xanthine oxidase
Accumulation
superoxide and hydrogen peroxide
• Ischemia and reperfusion induce transcription of multiple genes in
the hepatocyte via the transcription factors heat-shock factor &
nuclear factor kappa B
• Sinusoidal endothelial cells are exquisitely sensitive to reperfusion
injury, while hepatocytes become vulnerable following a significant
ischemic insult.

31. Clinical settings that increase the risk of
ischemic injury
• Preexisting liver disease and portal hypertension total hepatic
blood flow may already be reduced.
• Splanchnic blood that normally enters the liver may be shunted
through collateral circulation, thereby bypassing the liver ( potentially
resulting in varices)
• Chronic liver disease  Decreased functional hepatic mass in
patients vulnerable to development of decompensation when
there is added injury from an ischemic insult.

32. • Preexisting passive congestion of the liver  increased risk for ischemic
injury.
• Elevated central venous pressure transmitted to the hepatic veins
and small hepatic venules that drain the hepatic acini.
• Exudation of protein-rich fluid into the space of Disse due to the
sinusoidal congestion.
Leading to atrophy
Peri-sinusoidal edema
Impairs the diffusion of oxygen and flow of nutrients to hepatocytes

36. GRANULOMATOUS HEPATITIS
• Noncaseating - such as seen with sarcoidosis.
• Caseating – which are characterized by central necrosis.
• Fibrin-ring – in which epithelioid cells surround a vacuole that often
has an encircling fibrin ring. Conditions associated with fibrin-ring
granulomas include, Hodgkin lymphoma, cytomegalovirus (CMV),
leishmaniasis, hepatitis A, toxoplasmosis, giant cell arteritis,
Boutonneuse fever, and Q fever, and use of allopurinol
• Lipogranulomas – which contain a central lipid vacuole (usually seen
in patients who ingest mineral oil

37. High power view of a liver biopsy shows a noncaseating granuloma &
perigranulomatous mononuclear cell inflammation with hepatic necrosis.

39. Hepatic Amyloidosis
• Patients with hepatic amyloidosis often have concurrent symptoms of
fatigue, weight loss, and anorexia due to systemic amyloidosis.
• Clinical manifestations of hepatic amyloid deposition are usually mild
with hepatomegaly and elevated alkaline phosphatase being the
most frequent findings.
• Hepatomegaly57 to 83 %
• Associated ascites, this is more likely due to concurrent heart failure
or hypoalbuminemia.

40. Hepatic Amyloidosis
• Chronic liver disease and portal hypertension are rare.
• Elevated serum alkaline phosphatase level.
• In one study that included 98 patients with hepatic amyloidosis,
• Elevated ALP86%
• 61% had values of 500 int. units/L or more
• AST 37 percent of patients.

41. • Hepatic involvement90 percent of patients with AL amyloid
• 60 percent of patients with AA amyloidosis
• Clinical features of hepatic involvement in AA amyloidosis are similar
to those seen in AL amyloidosis.
• USG heterogeneous echogenicity.
• On CT scan, diffuse or focal regions of decreased parenchymal
attenuation with or without extensive calcification may be seen.

42. • Gastrointestinal amyloidosis should be suspected in patients with
– diarrhea
– weight loss
– gastrointestinal bleeding
– disorders known to be associated with amyloidosis
• plasma cell dyscrasia
• chronic inflammatory disease
• chronic renal failure on maintenance dialysis
• Systemic amyloid deposition (eg, proteinuria, hepatomegaly and
elevated alkaline phosphatase, restrictive cardiomyopathy, neuropathy,
unexplained edema, carpal tunnel syndrome, unexplained facial or neck
purpura, or macroglossia).

43. DIAGNOSIS
• colonoscopy and/or an upper endoscopy to obtain rectal or duodenal
mucosal
• Endoscopy – Non - specific
• fine granular appearance
• polypoid protrusions
• erosions
• ulcerations
• friability
• thickening of the wall
• Rarely, patients have tumor-forming deposits of amyloid, called
amyloidomas

47. HEPATIC SARCIODOSIS
• Most patientsasymptomatic/biochemical abnormalities (ALP/GGT)
• Abdominal pain and pruritus 15%
• hepatomegaly in 5 to 15 %
• Fever, weight loss, and jaundice < 5 %
• Cirrhosis 6 %
• cholestatic liver disease with diffuse intrahepatic biliary strictures
• Portal hypertension 3 %

49. • Typically, the majority of biopsy specimens greater than 2 cm in length
will have noncaseating granulomas that are often located along the
portal tract.
• As conditions other than sarcoidosis can cause granulomatous lesions in
the liver eg, tuberculosis, fungal infections, brucellosis, Q fever, primary
biliary cholangitis, Hodgkin disease, drug toxicity.
• Additional steps include identifying
• characteristic extrahepatic manifestations of sarcoidosis
• characterization of the granulomas within the liver
• examination of special stains/cultures for infectious organisms,
• exclusion of malignancy and drug-induced granulomas.

50. Postoperative jaundice
• Postoperative jaundice, the presence of bilirubin elevation with or
without clinical icterus appearing in the period following surgery,
occurs as a result of numerous causes.
• Pre-hepatic  overproduction of bilirubin such as from hemolysis or
a resolving hematoma.
• Intrahepatic  Injury to hepatocytes or biliary epithelial cells
(hepatic ischemia, infection, and drug toxicity)
• Post-hepatic  obstruction of the extrahepatic biliary tree
eg: Choledocholithiasis, CBD injury

51. Benign postoperative jaundice
• Term encompasses a multitude of potentially contributing causes
• Diagnosis of exclusion
• Despite the name, the course is not always benign.
• Prognosis depends mainly upon the underlying condition.
• In those who recover, jaundice will resolve gradually over weeks to
months.

53. Sepsis Induced Cholestasis
52 patients with toxic shock syndrome caused by Staphylococcus aureus–
related infections related to tampon use were studied in one case series;
at least 50% of these patients had hyperbilirubinemia and transamintis
thought to be related to the bacterial exotoxin production

54. Intrahepatic cholestasis of pregnancy
• occurs in the second and third trimester and is characterized by
pruritus and an elevation in serum bile acid concentrations.
• PATHOGENESIS - unknown
• Genetics — Genetic factors could explain familial cases and the
higher incidence in some ethnic groups.
• The ABCB4 gene encoding the multidrug resistance 3 (MDR3) protein
(a canalicular phospholipid translocator) is primarily involved in a
subtype of progressive familial intrahepatic cholestasis called PFIC3

55. Estrogens and progesterone
• Estrogens are known to cause cholestasis in both experimental and
clinical conditions, and a role in ICP is likely.
• ICP 3RD trimester when serum concentrations of estrogen reach
their peak.
• common in twin pregnancies estrogens than singleton pregnancy
• Alterations in progesterone metabolism, and the administration of
progesterone may be a risk factor for ICP

56. CLINICAL MANIFESTATIONS
• Intolerable generalized
pruritus, predominates on the
palms and the soles of the
feet and is worse at night
• Abdominal pain is
uncommon.
• Encephalopathy or other
stigmata of liver failure are
unusual, and their presence
should initiate a search for
other causes of liver disease.
• Jaundice occurs in less than
10 percent, typically after
the onset of itching.

57. Post–Bone Marrow Transplant Syndromes
• Veno-occlusive disease (VOD)  20 to 30 days after HSCT
• incidence of 10% to 60% (type and dosage of conditioning regimen)
• Exact mechanism of VOD is unclear
• Damage occurs in the hepatic venulesobliteration and necrosis of
the centrilobular zones of the liver
• Prior HSCT or who received abdominal irradiation or conditioning
regimens with busulfan/melphalan, or who have known underlying
liver diseases are more likely to develop VOD/SOS complications
post-HSCT.

58. Post–Bone Marrow Transplant Syndromes
• Jaundice
• Abdominal pain from capsular
stretching caused by hepa-
tomegaly
• Ascites as outflow obstruction
ensues.
• Bilirubin levels are generally > 2
mg/dL.
• Diagnosis  clinically
• Treatment
Diuretics
salt restriction
removal of any potential
hepatotoxic agents

59. Post–Bone Marrow Transplant Syndromes
VOD/SOS
• Usually hepatocellular
injury alone
GVHD
• occurs 3 weeks post-HSCT
• Systemic complications with
hepatocellular injury
VOD/SOS v/s GVHD  Transjugular liver biopsy
Treatment of the latter involves more aggressive immunosuppressive
regimens that would be ineffective for the former diagnosis