in details catabolic process of heme

1. HEME CATABOLISM

2. HEME CATABOLISM
•In one day, 70 kg human turns over = 6 gr of Hb
•Hb heme iron_free porphyrin
iron (reuse)
globulin amino acid (reuse)
~

3. • Heme is the source of bile pigments .
• Iron free porphrin of heme is degraded in RES
(liver,spleen bone_marrow) by microsomal heme
oxygenase system.
• Humans have at least 3 izoenzyems of heme oxygenase
(HO).

4. • HO-1 highyl regulated, induced by a wide
range of stress conditions (shear stress,
angiogenesis, hypoxia, heat shock, UV
light, H2O2)
• HO-2 MAİNLY İN BRAİN γ TESTES
• HO-3 NOT WELL CHARACTERİZED
• Iron is oxidized to ferric form HEMIN

6. • Hemin is reduced to heme by NADPH.
• O2 is added to α_methenyl bridge
between pyroles I and II of the porphyrin.
• Ferrous iron is again oxidized to ferric
form.
• O2 is added, Fe is released, CO is
produced, tetrapyrole ring is split to form
biliverdin (green).
+3

7. • In animals biliverdin reductase reduces the
methenly bridge between pyrole III and IV
to a methylene group to produce bilirubin.
(yellow pigment)
• 1 gr Hb 35 mg biliburin
• Daily bilirubin formation in human adults =
250-350mg (from Hb +ineffective
erytropoiesis+cyt P450)

8. • The CO produced by heme oxygenase is
toxic at high concentrations, however at
very low concentrations generated during
heme degradation, it has regulatory and/or
signalling functions, it acts as a
vasodilatator, less potent than NO.
• Low levels of CO have regulatory effects
on neurotransmission .

9. • Bilirubin is the most abundant antioxidant
in mammalian tissues and is responsible
for the most of the antioxidant activity in
serum.
• İts protective effects are important in the
developing brain of newborn infants

10. • Bilirubin formed in peripheral tissues is transported to
liver by albumin
• IN LIVER:
1)Uptake of bilirubin by liver paranchmal cells
2)conjugation of bilirubin with glucuronate in endoplasmic
reticulum
3)secretion of conjugated bilirubin into bile

12. • Uptake of bilirubin by liver
• Bilirubin is only sparingly soluble in water
• İts solubility in plasma is increased by
noncovalent binding to albumin
• Albumin has one high affinity site and one
low affinity site for bilirubin
• In 100 ml plasma = 25 mg bilirubin can be
tightly bound to albumin at high affinity site

13. • Antibiotics and other drugs compete with
bilirubin to bind to high_affinity site of albumin.
• In liver, bilirubin is removed from albumin and
taken up at the sinusoidal surface of
hepatocytes by a facilated transport system.
• In the hepatocytes bilirubin binds to cytosolic
proteins :
ligandin (a family of glutathione s-transferases)
and protein γ_to be kept solubilized prior to
conjugation.

14. Conjugation of bilirubin with
glucuronic acid
• Bilirubin is non_polar.
• Hepatocytes convert bilirubin to a polar
form by adding glucuronic acid to it
(conjugation)
• Enzyme: glucuronosyl transferase
• Location:endoplasmic reticulum
• Glucuronosyl donor:UDP_GLUCURONİC
ACİD

15. • Bilirubin monoglucuronide is an
intermediate, subsequently converted to
diglucuronide.
• Phenobarbital induces
UDP_glucuronosyl_transferase activity

17. Secretion of conjugated bilirubin
into bile
• Active transport mechanism
• Rate-limiting for the entire hepatic bilirubin
metabolism
• MRP_2 (multidrug resistance like protein
2)
= MOAT(multi specific organic anion
transporter)
Location:plasma membrane of the bile
canalicular membrane

18. • A member of the family of ATP_binding cassette
(ABC) transporters
• Inducible by phenobarbital
• Conjugation γ excretion systems behave as a
coordinated functional unit.
• Conjugated bilirubin reaches the terminal ileum
and large intestine.
• The glucuronides are removed by
β_glucuronidases (specific bacterial enzymes)

19. • The pigment is reduced by intestinal
bacteria (fecal flora) to urobilinogen
(colorless tetrapyrolic compound)
• A small portion of urobilinogen is
reabsorbed and reexcreted through the
liver: ENTEROHEPATİC UROBİLİNOGEN
CYCLE

20. • Some urobilinogen is reabsorbed into the
blood and transported to the kidney, where
it is oxidized to urobilin(the compound that
gives urine its yellow color).
• Urobilinogen remaining in the intestine is
converted to stercobilin, which gives the
red_brown color to feces .

21. Jaundice is a yellowish discoloration of the skin and mucous membranes caused
by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about
2 to 3 mg/dL (34 to 51 micromol/L).
Pathophysiology of Jaundice
Most bilirubin is produced when hemoglobin (Hb) is broken down into
unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to
albumin in the blood for transport to the liver, where it is taken up by
hepatocytes and conjugated with glucuronic acid to make it water soluble.
Conjugated bilirubin is excreted in bile into the duodenum. In the intestine,
bacteria metabolize bilirubin to form urobilinogen. Some urobilinogen is
eliminated in the feces, and some is reabsorbed, extracted by hepatocytes,
reprocessed, and re-excreted in bile.

22. Mechanisms of hyperbilirubinemia
Hyperbilirubinemia may involve predominantly unconjugated or conjugated
bilirubin.
Unconjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:
 Increased production
 Decreased hepatic uptake
 Decreased conjugation
Conjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:
1. Dysfunction of hepatocytes (hepatocellular dysfunction)
2. Slowing of bile egress from the liver (intrahepatic cholestasis)
3. Obstruction of extrahepatic bile flow (extrahepatic cholestasis)
Consequences
Outcome is determined primarily by the cause of jaundice and the presence and
severity of hepatic dysfunction. Hepatic dysfunction can result in coagulopathy,
encephalopathy, and portal hypertension (which can lead to gastrointestinal
bleeding).

24. Etiology of Jaundice
Although hyperbilirubinemia can be classified as predominantly unconjugated or
conjugated, many hepatobiliary disorders cause both forms.
Many conditions, including use of certain drugs, can cause jaundice, but the
most common causes overall areInflammatory hepatitis (viral hepatitis,
autoimmune hepatitis, toxic hepatic injury)
Alcohol-related liver disease
Biliary obstruction

28. Evaluation of Jaundice
History
History of present illness should include onset and duration of jaundice.
Hyperbilirubinemia can cause urine to darken before jaundice is visible. Therefore,
the onset of dark urine indicates onset of hyperbilirubinemia more accurately than
onset of jaundice. Important associated symptoms include fever, prodromal
symptoms (eg, fever, malaise, myalgias) before jaundice, changes in stool color,
pruritus, steatorrhea, and abdominal pain (including location, severity, duration,
and radiation). Important symptoms suggesting severe disease include nausea and
vomiting, weight loss, and possible symptoms of coagulopathy (eg, easy bruising
or bleeding, tarry or bloody stools).
Review of systems should seek symptoms of possible causes, including weight
loss and abdominal pain (cancer); joint pain and swelling (autoimmune or viral
hepatitis, hemochromatosis, primary sclerosing cholangitis, sarcoidosis); and
missed menses (pregnancy).

29. Past medical history should identify known causative disorders, such as
hepatobiliary disease (eg, gallstones, hepatitis, cirrhosis); disorders that can cause
hemolysis (eg, hemoglobinopathy, glucose-6-phosphate dehydrogenase [G6PD]
deficiency); and disorders associated with liver or biliary disease, including
inflammatory bowel disease, infiltrative disorders (eg, amyloidosis, lymphoma,
sarcoidosis, tuberculosis), and HIV infection or AIDS.
Drug history should include questions about use of drugs or exposure to toxins
known to affect the liver (see table Some Drugs and Toxins That Can Cause
Jaundice) and about vaccination against hepatitis.
Surgical history should include questions about previous surgery on the biliary
tract (a potential cause of strictures).
Social history should include questions about risk factors for hepatitis (see table
Some Risk Factors for Hepatitis), amount and duration of alcohol use, injection
drug use, and sexual history.
Family history should include questions about recurrent, mild jaundice in family
members and diagnosed hereditary liver disorders. The patient’s history of
recreational drug and alcohol use should be corroborated by friends or family
members when possible.

30. Physical examination
Vital signs are reviewed for fever and signs of systemic toxicity (eg, hypotension,
tachycardia).
General appearance is noted, particularly for cachexia and lethargy.
Head and neck examination includes inspection of the sclerae and tongue for
icterus and the eyes for Kayser-Fleischer rings (best seen with slit lamp). Mild
jaundice is best seen by examining the sclerae in natural light; it is usually
detectable when serum bilirubin reaches 2 to 2.5 mg/dL (34 to 43 micromol/L).
Breath odor should be noted (eg, for fetor hepaticus).
The abdomen is inspected for collateral vasculature, ascites, and surgical scars.
The liver is palpated for hepatomegaly, masses, nodularity, and tenderness. The
spleen is palpated for splenomegaly. The abdomen is examined for umbilical
hernia, shifting dullness, fluid wave, masses, and tenderness. The rectum is
examined for gross or occult blood.

31. Cause of jaundice:
• Acute jaundice in the young and healthy suggests acute viral hepatitis,
particularly when a viral prodrome, risk factors, or both are present; however,
acetaminophen overdose is also common.
• Acute jaundice after acute drug or toxin exposure in healthy patients is likely
to be due to that substance.
• A long history of heavy alcohol use suggests alcohol-related liver disease,
particularly when typical stigmata are present.
• A personal or family history of recurrent, mild jaundice without findings of
hepatobiliary dysfunction suggests a hereditary disorder, usually Gilbert
syndrome.
• Gradual onset of jaundice with pruritus, weight loss, and clay-colored stools
suggests intrahepatic or extrahepatic cholestasis.
• Painless jaundice in older patients with weight loss and a mass but with
minimal pruritus suggests biliary obstruction caused by cancer.

32. Men are checked for testicular atrophy and gynecomastia.
The upper extremities are examined for Dupuytren contractures.
Neurologic examination includes mental status assessment and evaluation for
asterixis (a characteristic flapping tremor of the hands).
The skin is examined for jaundice, palmar erythema, needle tracks, vascular
spiders, excoriations, xanthomas (consistent with primary biliary cholangitis),
paucity of axillary and pubic hair, hyperpigmentation, ecchymoses, petechiae, and
purpura.
The following findings are of particular concern:
 Marked abdominal pain and tenderness
 Altered mental status
 Gastrointestinal (GI) bleeding (occult or gross)
 Ecchymoses, petechiae, or purpura

35. Finding
Possible Causes
Risk factors
Alcohol use (heavy)
Alcohol-related liver disease, including alcoholic
hepatitis and cirrhosis
Gastrointestinal cancer Extrahepatic biliary obstruction
Hypercoagulable state Hepatic vein thrombosis (Budd-Chiari syndrome)
Inflammatory bowel disease Primary sclerosing cholangitis
Pregnancy
Intrahepatic cholestasis, steatohepatitis (acute
fatty liver due to pregnancy)
Previous cholecystectomy
Biliary stricture
Retained or recurrent common duct stone
Recent surgery
Ischemic hepatitis
Benign postoperative intrahepatic cholestasis
Lengthy cardiac bypass surgery
Findings Suggesting a Cause of Jaundice

36. Symptoms
Colicky right upper quadrant, right
shoulder, or subscapular pain (current
or previous)
Choledocholithiasis
Constant right upper quadrant pain
Acute alcoholic or viral hepatitis,
acute cholangitis
Dark urine Conjugated hyperbilirubinemia
Joint pain, swelling, or both
Hepatitis (autoimmune or viral)
Hemochromatosis
Primary sclerosing cholangitis
Sarcoidosis
Nausea or vomiting before jaundice
Acute hepatitis
Common bile duct obstruction by a
stone (particularly if accompanied by
abdominal pain or rigors)
Pruritus and clay-colored stools
Intrahepatic or extrahepatic cholestasis,
possibly severe if stools are clay-
colored
Viral prodrome (eg, fever, malaise,
myalgias)
Acute viral hepatitis

37. Physical examination
Abdominal collateral vasculature, ascites, and
splenomegaly
Portal hypertension (eg, due to cirrhosis)
Cachexia in a patient with a hard, lumpy liver Metastases (common)
Diffuse lymphadenopathy in a patient with acute
jaundice
Infectious mononucleosis
Diffuse lymphadenopathy in a patient with
chronic jaundice
Lymphoma, leukaemia
Dupuytren contractures, palmar erythema, paucity
of axillary and pubic hair, and vascular spiders
Alcohol-related liver disease
Gynecomastia and testicular atrophy Alcohol-related liver disease, anabolic steroid use
Hyperpigmentation Hemochromatosis, primary biliary cholangitis
Kayser-Fleischer rings Wilson disease
Needle marks Hepatitis B or C
Resolving hematoma Extravasation of blood into tissues
Xanthomas Primary biliary cholangitis