A.

Preface

The word jaundice comes from the French word jaune, which means
yellow. Jaundice is a yellowish staining of the skin, sclera, and mucous
membranes by bilirubin, a yellow-orange bile pigment. Bilirubin is formed by a
breakdown product of heme rings, usually from metabolized red blood cells. The
discoloration typically is detected clinically once the serum bilirubin level rises
above 3 mg per dL (51.3 mol per L). Jaundice is not a common presenting
complaint in adults. When present, it may indicate a serious problem. The classic
definition of jaundice is a serum bilirubin level greater than 2.5 to 3 mg per dL
(42.8 to 51.3 mol per L) in conjunction with a clinical picture of yellow skin and
sclera.

Scleral tissue rich in elastin, which has a high affinity for bilirubin, so
jaundice in the sclera is usually a sign that is more sensitive to indicate jaundice
hyperbilirubinemia. Early signs are similar to hyperbilirubinemia is darker urine
color caused by ekresi bilirububin through the kidneys in the form of bilirubin
glukoronid. Jaundice striking greenish skin can be due to the partial oxidation
circulating bilirubin to biliverdin.

Bilirubin metabolism takes place in three phasesprehepatic, intrahepatic,

and posthepatic. Dysfunction in any of these phases may lead to jaundice. Patients
with jaundice may present with no symptoms at all (i.e., the condition is found
accidentally), or they may present with a lifethreatening condition. The wide
range of possibilities is based on the variety of underlying causes and whether
disease onset is quick or slow moving. Patients presenting with acute illness,
which is frequently caused by infection, may seek medical care because of fever,

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chills, abdominal pain, and flu-like symptoms. For these patients, the change in
skin color may not be their greatest concern. Patients with noninfectious jaundice
may complain of weight loss or pruritus. Abdominal pain is the most common
presenting symptom in patients with pancreatic or biliary tract cancers. Even
something as nonspecific as depression may be a presenting complaint in patients
with chronic infectious hepatitis and in those with a history of alcoholism.
Occasionally, patients may present with jaundice and some extrahepatic
manifestations of liver disease. Examples include patients with chronic hepatitis
and pyoderma gangrenosum, and patients with acute hepatitis B or C and
polyarthralgias.

B. Epidemiology

Jaundice is an uncommon complaint in emergency departments (Eds). The

National Hospital Ambulatory Medical Care Survey (NHAMCS) collects data on
the utilixation of ambulatory care service, including ED visits. Analysis of over 1
billion ED visits from 1995 to 2004 via the NHAMCS database reveals that about
400,000 patients had a chief complaint or a final diagnosis of jaundice. Fifty-four
percent of the patients in this sample were under 15 years of age. This means a
50,000 patient-per-year ED could expect to see 18-19 visits related to jaundice in
that time. These data may underistimate the true number as they fail to account for
patients who were jaundiced oh physical examination but had an alternative chief
complaint or final diagnosis.

The frequency an etiology af jaundice varies depending on the population

studied. A Dutch study of 702 adults presenting with jaundice over a two-year
period found 20% to be due to pancreatic or biliary carcinoma, 13% due to
gallstones, and 10% due to alcoholic cirrhosis. Forty percent of the cases in the
U.S are due to obstruction. In terms of non-obstructive jaundice, a retrospective
study of over 700 patients reported 22% to be due to sepsis or ischemic liver
injury, 13% to non-alcoholic liver disease, 9% to acute viral hepatits, and 4% to
drug-induced liver injury. This was a single-center study and the results may not
axtrapolate to all care settings.

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 C. Bilirubin metabolism

Bilirubin is a breakdown product of normal hemoglobin resulting from

erythrocytes elderly (aged 120 days), the ring after being released from the iron
heme and globin by the reticuloendothelial system, which is converted to
biliverdin the green ones. Furthermore biliverdin turns into bilirubin yellow.
Unconjugated bilirubin is not water soluble it is transported to the liver, and then
bound with albumin. Bilirubin is transported across the membrane into the
cytoplasm of hepatocytes sinusoid. The enzyme uridine diphosphate-glucuronyl
transferase unconjugated bilirubin conjugate which is not miscible with
glucuronic acid to form a water-soluble conjugated form. Conjugated bilirubin
then actively secreted into the bile canaliculus. At the terminal ileum and colon,
bilirubin is converted by bacterial enzymes activity into mesobilirubinogen,
stercobilinogen and urobilinogen is mostly excreted in the feces. Approximately
10-20% of urobilinogen is reabsorbed into the portal circulation. Furthermore,
apart from the small number reach the kidneys and liver excretion excreted in
urine.

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 D. Pathophysiology

There are three phases of bilirubin metabolisme; prehepatic (hemolytic),

intrahepatic, posthepatic (obstructive). The new division added two more phases
so that the stages of bilirubin metabolism into five phases, that is:

1. Bilirubin formation
2. Transport plasma
3. Liver uptake
4. Conjugation
5. Excretion bilier

Prehepatic Phase

1. Bilirubin formation

Around 250-300mg bilirubin or about 4 mg / kg body weight

per day are formed; 70-80% comes from the breakdown of red
blood cells mature, while the remaining 20-30% comes from other
hem protein mainly located in the bone marrow and liver. Most of
the protein is broken down into hem iron and intermediate products
to the intermediary enzyme biliverdin hemeoksigenase. Another

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 enzyme, biliverdin reductase, change the biliverdin to bilirubin.
This stage is particularly the case in the system reticuloendothelial
(mononuclear phagocytosis). Increased red blood cell hemolysis is
the main cause increased formation of bilirubin

2. Trasport plasma
Unconjugated bilirubin indirect is not soluble in water, hence
the transport of unconjugated bilirubin in plasma is bound to
albumin and can not pass through the glomerular membrane, and
therefore not appear in the urine. Bonds weakened in some
circumstances such as acidosis and some ingredients such as
certain antibiotics, salicylates compete in the binding site to
albumin.

Intrahepatic Phase
1. Liver uptake

The process of making conjugated bilirubin by the liver in

detail and the importance of binding proteins such as protein
ligandin or Y, is not clear. Bilirubin intake via active transport and
running fast, but not including albumin take

2. Conjugation
Free bilirubin concentrated in the liver cells conjugated with
glukoronidase acid forming diglukoronida or bilirubin conjugation
of bilirubin or bilirubin direk. This reaction is catalyzed by the
microsomal enzyme glukoroniltransferase produce a water soluble
bilirubin. In some circumstances this reaction produces only
bilirubin monoglukoronida, with the second glukoronik acid was
added to the bile duct through a different enzyme system, but the
reaction is not considered physiology.

Posthepatic Phase

1. Bilirubin excretion

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 Conjugated bilirubin is released into the canaliculus along with
other materials. Other organic anions or drugs can affect this
complex process. In the intestine, bacterial flora reduce the
bilirubin into stercobilinogen and removing a large part in the stool
which gives a brown color. Some is absorbed and released back
into the bile, and small amounts reach the urine as urobilinogen.
Kidneys can remove bilirubin diglukoronida but not bilirubin
unconjugated. This explains the dark color of urine typical of
hepatocellular disorders or intrahepatic cholestasis. Unconjugated
bilirubin is insoluble in water but soluble in fats, therefore can pass
the blood-brain barrier or into the placenta. In liver cells,
unconjugated bilirubin undergo conjugation with sugar through
glucoroniltransferase enzymes and bile soluble liquid.
1. Hyperbilirubinemia Unconjugated / Indirect
a. Over production
Increasing the amount of hemoglobin released from red blood
cells that are old or who have hemolysis will increase the
production of bilirubin. Destruction of erythrocytes cause
hyperbilirubinemia most often as a result of intravascular
hemolysis (an autoimmune disorder, microangiopathy or
hemoglobinopathies) or as a result of a large hematoma resorption.
Jaundice arising often called hemolytic jaundice. Bilirubin
conjugation and transfer take place normally, but the supply of
unconjugated bilirubin / indirect exceed the ability of liver cells. As
a result, increased indirect bilirubin in the blood. Because the
indirect bilirubin is not soluble in water it can not be excreted into
the urine and does not occur bilirubinuria. But the formation of
urobilinogen increased, resulting in increased urine excretion in
feces (dark color). Some of the causes of hemolytic jaundice:
abnormal hemoglobin (cickle cell anemia), red cell disorders
(spherocytosis heriditer), serum antibodies (Rh. Incompatible
transfusions), and severe tropical malaria.
b. Descrease in hepatic uptake

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 Intake of unconjugated bilirubin is done by separating it from
binding to the protein albumin and receiver. Some medications
such as acid flavaspidat, novobiocin can affect the uptake of this.
c. Descrease hepatic conjugated

Conjugation of bilirubin interference so that an increase of

unconjugated bilirubin. This is caused by a deficiency of the
enzyme glucuronyl transferase. Occurs in: Gilberth syndrome,
Crigler Najjar Syndrome I, Crigler Najjar Syndrome II.

2. Hyperbilirubinemia Conjugated / Direct

Hyperbilirubinemia conjugation / direk can occur due to
decreased excretion of bilirubin into bile. Impaired excretion of
bilirubin can be caused by abnormalities of intrahepatic and
extrahepatic, depending excretion of conjugated bilirubin by
hepatocytes bilirubin will cause re-entry into the systemic
circulation causing hyperbilirubinemia. Hepatocellular
abnormalities can be related to: hepatitis, cirrhosis, alcohol,
leptospirosis, cholestasis drug (CPZ), a substance the liver
yg.meracuni phosphorus, klroform, anesthetics and multiple liver
tumors. Jaundice in the last trimester of pregnancy viral hepatitis,
Dubin Johnson and Rotor syndrome, post-surgical jaundice.
Extrahepatic biliary tract obstruction will cause conjugated
hyperbilirubinemia accompanied bilirubinuria. Extrahepatic biliary
tract obstruction may be total or partial. Total obstruction may be
accompanied stools akolik. The commonest causes of extrahepatic
biliary obstruction is
Obstruction bile duct in liver: cirrhosis of the liver,
liver abscess, hepatokolangitis, primary and secondary
malignant tumor.
Obstruction within the bile duct lumen: gallstones,
ascaris.
Abnormalities in bile duct wall: congenital atresia,
traumatic stricture, bile duct tumor.

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 Pressure from the outside of the bile ducts: caput
pancreatic tumors, tumors of the ampulla Vatery,
pancreatitis, tumor metastasis in lig.hepatoduodenale.

E. Disorders that can be jaundice

Here are disorders that can cause jaundice:

1. Prehepatic causes of jaundice

a. Congenital red cell issues
i. Cell shape
Sickle cell disease
Hereditary spherocytosis
Hereditary elliptocytosis
ii. Enzyme
G6PD deficiency
Pyruvate kinase deficiency
iii. Haemoglobin
thalassemia
b. Autoimune haemolytic anaemia
c. Drugs
i. Penicillins
ii. sulphasalazine
d. Infections
i. Malaria
e. Mechanical
i. Metalic valve prostheses
ii. DIC
f. Transfusion reactions
g. Paroxysmal nocturnal haemoglobinuria
2. Intrahepatic causes of jaundice
a. Conjugated causes
i. Cirrhosis (see chronic liver disease for further causes)
ii. Malignancy
Primary metastases
iii. Viral hepatis
iv. Drugs
Hepatitis
o Isoniazid, rifampicin, atenolol, enalapril,
verapamil, nifedipine, amiodarone,
ketoconazole, cytotoxics, halothane
Cholestasis

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 o Ciclosporin, azathioprine,
chlorpromazine, cimetidine,
erythromycin, nitro, ibuprofen,
hypoglycaemics
v. Enzymes
Dubin-Johnson syndrome (DJS)
o Autosomal recessive (cMOAT gene)
with excretion of conjugated bilirubin
Leads to pigmented liver
o Increase in conjugated bilirubin with no
other enzyme changes
o High coproporphyrin
Rotor syndrome
o Similiar to DJS
o Liver not pigmented
o Normal coproporphyrin
b. Unconjugates causes on jaundice (sometimes classified as pre-
hepatic causes)
i. Gilberts syndrome
Congenital hypo-activity of conjugation enzyme
UGT-1. Benign and common (5%)
Normal LFTs except mildly elevated bilirubin,
especially in times of physiological stress/illness
Normal life expectancy
ii. Crigler-Najar syndrome
Autosomal recessive (type I) or dominant (type
II). Severe unconjugated hyperbilirubinemia
Congenital absence (I) or decrease (II) of
glucoronyl transferase
Normal liver histology
Treatment is liver transplant (only type II
survive to adulthood)
3. Posthepatic causes of jaundice
a. Biliary tree obstruction
i. Gallstones
ii. Compression e.g. pancreatitis, pancreatic tumor, lymph
nodes, biliary atresia
iii. Cholangiocarcinoma
iv. Post-operative stricture
b. Primary biliary cirrhosis

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 i. M:F = 1:9
ii. ANA and anti-centromere for prognosis (though more
association with CREST)
c. Primary scelosing cholangitis
i. 80% of PSC have UC
ii. ANCA, anti-smooth muscle antibodies
iii. Association with cholangicarcinoma
4. Pregnancy-associated jaundice
a. Obstetric cholestasis
i. 0.1-0.2% of pregnancies
ii. Presentation
Itching jaundice later
Raised liver markers, esp ALP
iii. Issues
Fetal mortality 3.5%
iv. Often recurs in further pregnancies
v. Treatment
Ursodeoxycholic acid
b. HELLP
i. Occurs in 1-2 out of 1000 pregnancies and 10-20% of
severe pre-eclamsia
ii. Leads to a variant of DIC
iii. Needs steroids and prompt delivery
iv. Maternal mortality 1-24%
c. Fatty liver of pregnancy
i. All LFTs including synthetic function go off
d. Hyperemesis gravidarum
e. Pre-eclamsia
i. Associated with abnormal LFTs in 20% cases
F. Differential Diagnosis
The differential diagnosis of jaundice is broad, and a precise diagnosis
is not always possible. For this reason, the EP has two primary responsibities: to
identify and stabilize patients with life-threatening causes of jaundice and to
provide an appropriate work-up for non-emergent cases.
Fulminant hepatic failure
Acute cholangitis
Massive hemolysis
Neonatal hyperbilirubinemia kernicterus
Acute fatty liver of pregnancy

Differential diagnosis of hepatocellular jaundice

Neoplasm Hepatocellular carcinoma
Cholangicarcinoma

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 Metastatis disease
Hereditary Wilsonss disease
Alpha -1- antitrypsin deficiency
Hemochromatosis
Miscellaneous Secondary biliary cirrhosis
Cryptogenic cirrhosis
Infections bacterial Tuberculosis (TB)
Leptospirosis
Syphilis
Abscesses
Brucellosis
Rickettsia
Whipples disease
Infection fungal Candida
Blastomyces
Coccodies
Histoplasmosis
cryptococcus
Infection parasitic Helminths - ascaris, clonorchis,
schistosomiasis, echinococcus
Protozoa amebiasis, plasmodia,
babesiosis, toxoplasmosis,
leishmaniasis
Toxic Medications
Alcohol
Chlorinated hydrocarbons
Amanita phalloides toxin
Aflatoxin
Vitamin A1
Arsenic
Pyrroliziadine alkaloids
Immunologic Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis

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 Nonalcoholic steatohepatitis

G. Diagnosis

Clinical
Approach
1. History of
illness
A complete medical history is the most important part of the
evaluation of patients with jaundice that can not be explained.
Important considerations include the use of a drug or chemical
exposure, either the doctor prescribed or over-the-counter,
complementary or alternative medicine such as herbal and perfomed
vitamins, or other drugs such as anabolic steroids. Patients should be

12
carefully questioned about the possibility of parenteral exposure,
including transfusion, intravenous and intranasal drug use, tattooing
and sexual activity. Other important questions include a history of the
last trip; exposure to people with jaundice; exposure to contaminated
food; Exposure hepatotoxins; alcohol consumption; the duration of
jaundice; and their accompanying symptoms such as arthralgia,
myalgia, rash, anorexia, weight loss, abdominal pain, fever, pruritus,
and changes in urine and feces. While none of the last symptoms are
specific to each of the requirements, they can suggest a specific
diagnosis. Their arthralgia and myalgia precede jaundice indicates
hepatitis, whether viral or drug-related. Jaundice with severe pain in
the right quadrant and chills show choledokolitiasis and ascending
cholangitis.

History of present illness/review Onset of jaundice

Abdominal pain
of symtoms
Nausea
Fever
Pruritis
Weight loss/gain
Bowel symtoms
Dark urine/pale stools
Past medical history HIV
Liver disease
IBD
Heart valve surgery
Autoimune disorders
Family history Liver disease
Neoplasm
Thalassaemia
Sickle cell
Medications Prescription medications (statins,
oral contraceptives)
Herbal remedies
Allergies
Social history Alcohol consumption
Travel history: viral hepatitis,
malaria
Occupation (chemical exposure)

2. Physical examination

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 General assessment should include assessment of nutritional
status of patients. Temporal and proximal muscle wasting disease
shows long as pancreatic cancer or cirrhosis. Stigmata of chronic
liver disease, including Spider nevi, palmar erythema,
gynecomastia, caput medusa, Dupuytren's contracture, enlarged
parotid glands and testicular atrophy are commonly seen in
alcoholic cirrhosis advanced stages (Laennec's) and sometimes in
other types of cirrhosis. Enlargement of the left supraclavicular
node (Virchow's node) or periumbilical nodule (Sister Mary
Joseph's nodule) showed abdominal malignancy. Jugular venous
distention, sign right-sided heart failure, showed liver congestion.
Right pleural effusion, ascites in the absence of clear, can be seen
in advanced stages of cirrhosis.
Abdominal examination should focus on the size and
consistency of liver, spleen is palpable and therefore enlarged, and
whether there is ascites. Patients with cirrhosis may have left lobe
enlarged and palpable under the xiphoid, and an enlarged spleen. A
liver nodules nodular or abdominal mass clearly indicate
malignancy. Enlargement of the liver that can be caused soft or
alcoholic hepatitis virus; infiltrative processes such as amyloid; or
more rarely, kongest acute liver secondary to right-sided heart
failure. Pain in the right upper quadrant with stops breathing during
inspiration (Murphy sign) indicate cholecystitis or sometimes
ascending cholangitis. Ascites with jaundice indicates either
cirrhosis or malignancy with peritoneal dissemination.

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C aput medusae

Clubbing
fingers

Ikterus

15
 Spider nevi

3. Laboratorium

When the physician meets with patients with jaundice, there is

a series of tests that can help in the initial evaluation. These include
serum total and direct bilirubin fractionation, aminotransferase,
alkaline phosphatase, albumin and prothrombin time test. Tests
enzymes [alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and alkaline phosphatase (ALP)] help in
distinguishing between processes hepatocellular and cholestatic
process is an important step in determining what additional
examination results indicated. Patients with hepatocellular process
generally have a disproportionate rise in aminotransferases than the
ALP. Patients with cholestatic processes have a disproportionate
rise in the ALP compared with aminotransferase. Bilirubin can be
clearly elevated in both hepatocellular and cholestatic conditions
and therefore are not always helpful in distinguishing between the
two.
In addition to the enzyme tests, all patients should have a
yellow additional blood tests, especially albumin levels and
prothrombin time to assess liver function. Low albumin levels
indicate chronic processes such as cirrhosis or cancer. Normal

16
 albumin level is suggestive of a process that is more acute as
hepatitis virus or koledokolitiasis. High prothrombin time indicates
a deficiency of vitamin K for prolonged jaundice and
malabsorption of vitamin K or significant hepatocellular
dysfunction. Failure to correct the prothrombin time with
parenteral administration of vitamin K showed severe
hepatocellular injury.
Results bilirubin, enzyme assays, albumin, and prothrombin
time test will usually indicate whether the patient has a disorder
yellow hepatocellular or cholestatic disease, as well as some
indication of the duration and severity of the disease. Cause and
evaluation of hepatocellular and cholestatic disease are very
different.
1. Complete blood count
2. Liver function test
3. Hepatitis serology test
4. Bilirubin
5. Test urine
6. Imaging
7. ERCP (endoscopic retrograd cholangiopankreatography)
8. MRCP (magnetic resonance Cholangiopankreatography)
9. Liver biopsy

Features Healthy Normal

Total Bilirubin Less than 1.00 mg
Conjugated Bilirubin Less than 0.15 mg
AST (SGOT) Less than 31 i.u/L
ALT (SGPT) Less than 35 i.u/L
Alkaline phosphatase Less than 112 i.u /L
GGT and 5 Nucleosidase, CDT Significantly in ALD
Urine Bilirubin Absent
Urine Urobilinogen In trace quantity

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 Urine Bile Salts Absent

Lab diagnosis of jaundice - DD

Features Prehepatic Intrahepatic Posthepatic

Unconjugated Normal Normal
Conjugated Normal
AST or ALT Normal Normal
Alkaline phos. and GGT Normal Normal
Urine bilirubin Absent Present Increased
Urobilinogen Increased Present Absent

Hepatits serologies

Hepatitis A Anti-HAV IgM

Hepatitis B Anti-HBc antibodies: (+) IgM for acute
infection, (+) IgG for previous or ongoing
infection
HbsAG
Anti-HBs: resolution or immunity
HbeAG: increased viral replication
Anti-Hbe: waning viral replication
Hepatitis C Anti-HCV
HCV RNA
Hepatitis D Anti-HDV
Hepatitis E IgM anti-HEV
Other viruses CMV, VZV, EBV, HSV

H. Management

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 Icterus treatment relies heavily on essentially the disease. Some of the
symptoms are quite disturbing eg, itching or pruritus on the state of intrahepatic
cholestasis, treatment of disease is essentially already sufficient.

1. Prehepatic

As mentioned in the previous section, some pre-hepatic

jaundice causes include hemolytic anemia, severe tropical malaria,
Gilbert's syndrome or Crigler Najjar syndrome.
Hemolytic anemia can be caused by a reaction tokosik-
immunology. Treatment for hemolytic anemia include prednisone 1-
2mg / kg, immunosuppressive drugs, and spleenektomi when it failed
with conservative therapy.
As for inherited diseases such as familial Gilbert's syndrome or
Crigler Najjar syndrome (glucuronyl transferase enzyme deficiency) is
a rare case. According to the literature, the treatment given is
Phenobarbital 5 mg / kg / day in the long term.

2. Hepatic

The cause of intra-hepatic jaundice frequently encountered in

clinical include viral hepatitis, cirrhosis, and hepatoma. Management
of the specifics of each disease is different according to the etiology.
Hepatitis is most commonly encountered in clinical and often
cause the appearance of jaundice is hepatitis A (transmitted through the
faecal-oral) and hepatitis B (transmitted through the blood). Hepatitis
A is a self limiting disease and there is no specific medicine for this
disease. While hepatitis B is a serious disease that if not treated with
due will cause long-term complications that bad. Various alternative
medicine that can be given for hepatitis B include lamivudine 100 mg /
day for 2 years, interferon, etc. Manifestations of jaundice in viral
hepatitis will disappear along with improved disease.
While hepatoma and cirrhosis are the two diseases are
interrelated and may be preceded by a history of chronic hepatitis

19
 before. On two of these disease conditions, treatment given merely
symptomatic. Liver transplant is the only definitive therapy can
provide satisfactory results.

3. Posthepatic

Basically the management of patients with obstructive jaundice

aims to eliminate the cause of the blockage or divert the flow of bile.
Such measures may include surgery eg removal of stone or tumor
resection.
If the cause is a tumor and surgery can not eliminate the cause
of obstruction because the tumor is then carried out actions to divert
the drainage of the bile flow.

Bibliography

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