2. Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte, derived from well-differentiated hepatocytes, generally leading to death within 6-20 months.
Frequently arises in the setting of cirrhosis, appearing years following the initial insult to the liver.
25% of patients have no history or risk factors for the development of cirrhosis.

3. Epidemiology
HCC is the fifth most common cancer and the third most frequent cause of cancer death worldwide, with an estimated 560,000 new cases per year.
There are strong etiologic associations with chronic hepatitis B virus (HBV), chronic hepatitis C virus (HCV), alcoholic cirrhosis, other causes of chronic liver disease, and dietary aflatoxin exposure.
In patients with underlying cirrhosis, males greatly outnumber females but in non-cirrhotic cases this sex difference is less striking.
In areas of high incidence the peak age is in the third and fourth decades of life but in Europe and North America most cases occur in the fifth and sixth decades.

4. The relative frequency of various tumors of the liver
Figure The relative frequency of various tumors of the liver. Note that metastases are by far the most frequent, particularly in the developed western world. Among the primary malignant tumors, hepatocellular carcinoma is the most frequent.

5. ETIOLOGY AND RISK FACTORS
Chronic hepatitis B
Chronic hepatitis C
Dietary aflatoxin exposure
Cirrhosis from alcohol and other chronic liver diseases
Familial and genetic influences on risk for hepatocellular carcinoma

6. Chronic hepatitis B
Cirrhosis develops in 0.1% to 2% of patients with chronic hepatitis B each year, depending on the duration of HBV replication, the severity of disease, and the presence of coexisting infections or alcohol use.
Certain HBV strains predominate in HCCs, suggesting that particular genotypes are more effective at initiating or promoting hepatocarcinogenesis.

7. Chronic hepatitis C
Genotype 1b is associated with more severe liver disease
Patients with active hepatitis, those with co-infections with HBV or human immunodeficiency virus (HIV) and those with other causes of chronic liver disease such as alcoholic liver disease are more likely to develop liver-related complications.
Patients with combined hepatitis B surface antigen positivity and chronic HCV infection are at particular risk for HCC.
After surgical resection of HCC, the presence of active hepatitis and hepatitis C viremia are risk factors for tumor recurrence.

8. Dietary aflatoxin exposure
Aflatoxin (derived from aspergillus flavus toxin) is a mycotoxin produced by two fungal species, Aspergillus flavus and Aspergillus parasiticus.
There are at least 13 different types of aflatoxin, with aflatoxin B1 considered the most toxic.
Aflatoxins are metabolized in the liver by the cytochrome P450 and glutathione S-transferase enzyme systems.
Aflatoxin B1 is a procarcinogen that is converted in the liver to the mutagenic metabolite aflatoxin B1-8,9-exo-epoxide by hepatic microsomal cytochrome P450.

9. Cirrhosis from alcohol and other chronic liver diseases
The HCC risk is higher for individuals with chronic hepatitis and ongoing hepatocellular injury.
Individuals who stop drinking significantly reduce their risk for HCC.
Patients with nonalcoholic steatohepatitis and cirrhosis who achieve reduced hepatic steatosis and those with hereditary hemachromatosis and cirrhosis who are iron depleted by phlebotomy have a reduced risk for HCC.
Certain causes of cirrhosis, such as autoimmune hepatitis, carry a relatively low risk for HCC.

10. Familial and genetic influences on risk for hepatocellular carcinoma
The biologic basis for this phenomenon is unknown.
Epidemiologic studies have suggested either the presence of a recessive allele that contributes to risk for HCC or a familial predisposition to a prolonged HBV replication phase.
Genetic polymorphisms of the carcinogen-metabolizing enzymes cytochrome P450 (CYP), glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT2), as well as p53 polymorphisms, may contribute to familial risk for HCC.

11. The molecular mechanisms of liver carcinogenesis
(1) the use of chemical tumor initiators and promoters in animal models (2) studies of growth factors and their signaling pathways (3) transgenic mouse models overexpressing cytokines, growth factors or oncogenes (4) studies of immune-mediated mechanisms of hepatocellular injury (5) analysis of the molecular genetic changes that occur in HCCs, including studies of chromosomal allelic imbalance, comparative genomic hybridization, restriction landmark genomic scanning and gene expression analysis using cDNA microarrays (6) studies of the molecular consequences of HBV integration and the interaction of the protein products of HBV and HCV with host cell processes

13. Macroscopic
The photo above shows a view of a longitudinal slice taken through the full length of the liver. The closer view, shows tumor at the top, cirrhotic liver at the bottom and a fibrous reaction in between.
Hepatocellular carcinomas can have a variety of gross patterns, including multinodular/multifocal, such as this one.

14. Histology
Histology is quite variable, ranging from well-differentiated tumors to anaplastic tumors.
The fibrolamellar subtype is associated with a better prognosis, possibly because it is not associated with cirrhosis and is more likely to be resectable.
The presence of intracellular bile or staining for AFP may be helpful in distinguishing hepatocellular carcinoma from other hepatic malignancies (eg, cholangiocarcinoma).
Immunohistochemistry using the marker Hep-Par 1 may aid in the diagnosis.
Aberrations of chromosome 1 and 8 are common features of hepatocellular carcinoma that can be detected by fluorescent in situ hybridization (FISH) technique. The role of FISH in the diagnosis of hepatocellular carcinoma is still under investigation.

15. Microscopic
Immunohistochemical analysis A, H&E staining of poorly differentiated hepatocellular carcinoma. B, poorly differentiated hepatocellular carcinoma immunostained with the mAb A7241A (serial section adjacent to the H&E-stained specimen A). Magnification, ×40. Strong staining was observed in hepatocellular carcinoma but not in noncancerous areas. C, well-differentiated hepatocellular carcinoma. Magnification, ×200. D, moderately differentiated hepatocellular carcinoma. Magnification, ×200. E, poorly differentiated hepatocellular carcinoma. Magnification, ×200. The epithelium of poorly differentiated hepatocellular carcinoma was labeled strongly with the mAb A7241A

16. Symptoms
HCC initially may escape clinical recognition because it occurs in patients with underlying cirrhosis and the symptoms and signs may suggest progression of the underlying disease.
decompensation of cirrhosis
tumoral symptoms
cholestasis
fever of unclear etiology
paraneoplastic phenomena
metastatic presentation

17. Decompensation of cirrhosis
ascites
refractory variceal bleeding
the diffuse infiltrating cancers further worsen hepatic function, resulting in:
hyperbilirubinemia
coagulopathy
encephalopathy

18. Hepatic carcinoma, primary
Hepatic carcinoma, primary. Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, hepatocellular carcinoma (HCC), and portal vein occlusion.

19. Tumoral symptoms
- less common than the presentation of hepatic decompensation
anorexia
weight loss
general malaise
painful hepatomegaly
- the pain is usually acute, limited in time (less than 24 hours) and assumed to be biliary colic

20. Cholestasis
tumor-associated extrinsic compression of the large bile ducts
tumor invasion of the large bile ducts
miliary metastasis throughout the liver
hemobilia and gastrointestinal bleeding
disproportionately high serum transaminases in addition to hyperbilirubinemia and jaundice

21. Fever unusual presentation of HCC
the febrile episodes may be discrete episodes and associated with leukocytosis
night sweats are common in advanced HCC and portend a poor prognosis

22. Paraneoplastic phenomena
are rare
hypercalcemia
erythrocytosis
hypoglycemia
thrombophlebitis migrans
arterial hypertension
the syndrome of watery diarrhea, hypokalemia and achlorhydria

23. Metastatic presentation
one metastatic complication of HCC is dyspnea due to tumor pulmonary emboli
another is headache associated with pituitary metastases
Common sites for HCC metastases include the diaphragm with associated pleural effusions, bone metastases with pain and regional lymph node metastases, which may be associated with abdominal discomfort.
Abdominal pain in patients with HCC is a poor prognostic symptom and usually indicates advanced disease.

24. Physical findings Jaundice Ascites Hepatomegaly
Alcoholic stigmata (Dupuytren contracture, spider angiomata)
Asterixis
Pedal edema
Periumbilical collateral veins
Enlarged hemorrhoidal veins

25. Differential diagnosis
Cholangiocarcinoma
Cirrhosis
Hepatocellular adenoma
Dysplastic nodules in cirrhosis
Fibrous nodular hyperplasia
Metastatic disease
Primary hepatic lymphoma
Hepatoblastoma
Hemangioma

26. Haematological and biochemical indices
Apart from alpha-fetoprotein, are non-specific and reflect the space-occupying lesion as well as the underlying cirrhosis present in about 80% of cases
Alpha-fetoprotein is a glycoprotein synthesized by the fetal liver and its plasma concentrations reach their maximum at the end of the first trimester (3 to 4 mg/ml) and then decline.
Raised levels are found in about 80% of patients with hepatocellular carcinoma
Concentrations above 500 ng/ml in a patient with liver disease are highly suggestive
Other tumour markers for hepatocellular carcinoma have been described in the serum, including an abnormal vitamin B 12 binding protein which is usually present with the fibrolamellar histological variant.

27. Results consistent with cirrhosis:
total bilirubin
aspartate aminotransferase (AST)
alkaline phosphatase
albumin
prothrombin time

28. Real-time ultrasound
This is a sensitive and specific test and picks up hepatocellular carcinoma in 85 to 90% of cases.
False-negative results usually occur in patients with tumours of less than 2 cm in diameter.
Is frequently used to screen high-risk populations and should be the first test if HCC is suspected.

29. Ultrasound examination of the liver
Figure Ultrasound examination of the liver showing a 5 × 10 cm hypoechoic mass (between markers). Ultrasound is one of the most sensitive methods for detecting tumors within the liver and is also relatively inexpensive and noninvasive [19]. Hepatocellular carcinoma often has echogenicity different from that in the remainder of the liver. Thus, small tumors are often hyperechoic with a thin hypoechoic rim. With time, and as the tumor grows, the whole tumor often becomes hypoechoic, and finally, when the tumor is large, it often has mixed echogenicity.
References:
[19]. Kobayashi K, Sugimoto T, Makino H, et al. Screening methods for early detection of hepatocellular carcinoma. Hepatology

30. Abdominal computed tomographic (CT) scanning
This technique is probably no more accurate in detecting hepatocellular carcinoma than ultrasound and should be reserved for cases in which doubt persists.
Sensitivity can be increased by contrast enhancement.
Dynamic spiral contrast-enhanced CT scanning is even more sensitive.
Arterial phase contrast-enhanced CT scan shows dominant hepatocellular carcinoma in peripheral right lobe (arrow). Multifocal enhancing tumor (asterisk) can be seen throughout remainder of liver.

31. Contrast-enhanced CT scan
Figure Contrast-enhanced computed tomographic (CT) scan of the liver in a patient with hepatocellular carcinoma (HCC). Left panel shows a small, shrunken, irregular liver with no obvious tumor masses. Right panel shows CT scan repeated in the same subject 2 weeks after intra-arterial infusion of Lipiodol (Therapex, Canada). At that point, a small HCC can be seen in the posterior aspect of the right lobe because it continues to contain Lipiodol. CT scanning is relatively sensitive and, when combined with prior infusion of Lipiodol, is an extremely sensitive method of detecting HCC. The oily contrast medium Lipiodol, which is also used for lymphangiograms, appears to be selectively retained within HCC tissue for several weeks. Thus, if CT scan is done 2 to 3 weeks after intra-arterial infusion of Lipiodol, very small tumors may sometimes be viewed [20].
References:
[20]. Kuroda C, Sakurai M, Monden M, et al. Limitation of transcatheter arterial embolization using iodized oil for small hepatocellular carcinoma. Cancer

32. Hepatic arteriography
As the major vascular supply to a hepatocellular carcinoma is usually arterial, diagnostic changes are seen in a high proportion of cases.
Information gained on the anatomical distribution of the tumour and the vascular anatomy is essential if surgical resection or transplantation is being contemplated and consideration can also be given at the time of arteriography to intra-arterial chemotherapy and hepatic artery embolization.
64-year-old woman with hepatocellular carcinoma. Celiac arteriogram shows standard hepatic artery anatomy.

33. Imaging modalities in diagnosis of hepatocellular cancer
Figure Relative sensitivity of various imaging modalities in diagnosis of hepatocellular cancer (HC). Some of the typical clinical features of HC include abdominal swelling, right upper quadrant pain, weight loss, and apparent worsening of liver disease in patients known to have cirrhosis. This tumor only becomes clinically apparent, however, when it is far advanced. When patients present with these symptoms they usually have extensive tumor involvement within the liver as well as distant metastases. The use of radiologic imaging studies has allowed detection of HC at an earlier stage, often before the development of symptoms. CT­computed tomography; MRI­magnetic resonance imaging. (Adapted from Di Bisceglie [2].)
References:
[2]. Stromeyer FW, Ishak KG, Nodular transformation (nodular `regenerative´ hyperplasia) of the liver. Hum Pathol

34. Magnetic resonance imaging (MRI)
This technique, particularly with the addition of a contrast agent, is proving useful in identifying and characterizing focal liver masses.
Lesions that do not contain reticuloendothelial cells or hepatocytes (haemangiomas and metastases) do not have their signal intensities altered.

35. Liver biopsy
For definitive diagnosis, liver biopsy is essential, although this is not always possible because of the prolongation of the prothrombin time.
The diagnosis can be considered highly likely without liver biopsy proof if the alpha-fetoprotein level is greater that 500 ng/ml and the hepatic arteriogram shows a tumour circulation.
Biopsy may be conveniently done at the time of laparoscopy or ultrasonography and suspicious areas can be sampled under direct vision.
Because of the risk of tumour spread, biopsy is often avoided if curative resection or transplantation is planned.

36. Laparoscopy To permit liver biopsy under direct vision.
This approach has the additional advantage of sometimes identifying patients who have a localized resectable tumor suitable for partial hepatectomy.

37. Staging of hepatocellular carcinoma for selection of therapy
all patients should undergo a chest radiograph to exclude pulmonary metastases and at least two imaging studies to stage intrahepatic disease and exclude vascular invasion
ultrasound
contrast CT
contrast MRI
color-flow Doppler and ultrasound-guided FNA (portal vein thrombosis)

38. Other exams Chest radiography may demonstrate pulmonary metastases
Bone scanning and head CT scanning are of low yield in the absence of specific symptoms.
PET scan has been evaluated in the experimental setting, but, to date, its role is uncertain. Routine use of PET scan for diagnosis or staging of hepatocellular carcinoma is not recommended.

40. Hepatic carcinoma, primary
Hepatic carcinoma, primary. Unusual location of a bone metastasis from hepatocellular carcinoma (HCC).

41. TNM T1 - Solitary tumor without vascular invasion
T2 - Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
T3 - Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
T4 - Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
N0 - Indicates no nodal involvement
N1 - Indicates regional nodal involvement
M0 - Indicates no distant metastasis
M1 - Indicates metastasis presence beyond the liver

42. Stage grouping Stage I = T1 + N0 + M0 Stage II = T2 + N0 + M0
Stage IIIA = T3 + N0 + M0
Stage IIIB = T4 + N0 + M0
Stage IIIC = TX + N1 + M0
Stage IVB = TX + NX + M1

43. CLIP scoring system: Score of 0-2 is assigned for each of the 4 features listed below; cumulative score ranging from 0-6 is the CLIP score.
Child-Pugh stage
Stage A = 0
Stage B = 1
Stage C = 2
Tumor morphology
Uninodular and extension less than 50% = 0
Multinodular and extension less than 50% = 1
Massive and extension greater than 50% = 2
Alpha-fetoprotein
Less than 400 = 0
Greater than 400 = 1
Portal vein thrombosis
Absent = 0
Present = 1
- Estimated survival based on CLIP score: Patients with a total CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.

44. Complications
Symptoms of hepatic failure may signify tumor recurrence and/or progression.

45. Screening
Patients with an increased risk of developing hepatocellular carcinoma, such as those with cirrhosis or chronic HBV or HCV infection, should be considered for regular screening by alpha-fetoprotein assay and abdominal ultrasonography.

46. Prognosis
This is a highly malignant tumour and the mean survival in most series is around 4 to 6 months.
Patients with cirrhosis have a poorer prognosis than those without.
Encapsulated tumours and the fibrolamellar histological variant, as well as small tumours picked-up at screening, have a better prognosis.

49. Essentials
Jaundice is the clinical sign of hyperbilirubinaemia, and hence usually indicates disease of the liver or biliary tree.
The pigment in the tissues in best seen as yellowing of the sclera; eventually the skin and soft palate become tinted, but not saliva or sputum.
The urine usually becomes dark.
Rarely, carotenaemia, from eating excessive carrots or vitamin A, can mimic jaundice, but its colour is more prominent in the palms than the sclera.

50. Definition
Jaundice (icterus) is the yellow discoloration of skin, sclera and mucous membranes caused by the excessive accumulation of bilirubin pigments.
It is usually apparent when bilirubin levels exceed 3 mg/dL or 50 μmol/L.

51. Pathophysiology
Hyperbilirubinemia results from one or more derangements in:
Formation
Conjugation
Excretion
Cholestasis is characterized by the constellation of physiological, morphologic and clinical manifestations that result from the impairment of the bile excretory system in the liver and biliary tree. Reduced bile flow resulting in the accumulation of conjugated bilirubin, bile salts and cholesterol in the blood is the hallmark of cholestasis.

52. Bilirubin metabolism Bilirubin is the end product of heme degradation.
Under normal circumstances, bilirubin is removed from the circulation rapidly and efficiently by hepatocytes.
Hepatocellular uptake
Intracellular binding
Conjugation
Biliary excretion

55. Pathophysiology excess bilirubin formation altered uptake
defective conjugation
diminished excretion

58. History
Dark urine and, less commonly, pale stools indicate cholestasis.
Many drugs, including alcohol, can be a cause of unconjugated and conjugated hyperbilirubinaemia and should be rigorously enquired about.
Fever (hepatitis, cholangitis, abscesses), travel (hepatitis, amoebiasis), sexual history (hepatitis A, B, or C), surgery and anaesthesia (postoperative jaundice; biliary tract disease), herbal medicines (e.g. West Indian teas, Chinese herbs), transfusions and blood products (hepatitis B or C) can be important clues.

59. Symptoms the skin and whites of the eyes appear yellow
urine is often dark because excess bilirubin is excreted through the kidneys.
itching, light-colored stools or other symptoms, depending on the cause of jaundice.
loss of appetite, nausea, vomiting, fever
blockage of bile may result in abdominal pain and fever
Stigmata of chronic liver disease (e.g. spider naevi, facial telangietases, parotid enlargement, Dupuytren's contractures, muscle wasting, hepatosplenomegaly, and ascites) are important, but do not define the cause of jaundice.

60. Pre-hepatic Laboratory findings include:
Urine: no bilirubin present, urobilirubin > 2 units (i.e., hemolytic anemia causes increased heme metabolism; exception: infants where gut flora has not developed).
Serum: increased unconjugated bilirubin.
Kernicterus is associated with increased unconjugated bilirubin

61. Hepatic Laboratory findings depend on the cause of jaundice.
Urine: Conjugated bilirubin present, urobilirubin > 2 units but variable (except in children). Kernicterus is a condition not associated with increased conjugated bilirubin.

62. Post-hepatic
The presence of pale stools and dark urine suggests an obstructive or post-hepatic cause as normal feces get their color from bile pigments.
Patients also can present with elevated serum cholesterol, and often complain of severe itching or "pruritus" because of the deposition of bile salts.

63. Function test
Pre-hepatic Jaundice
Hepatic Jaundice
Post-hepatic Jaundice
Total bilirubin
Normal / Increased
Increased
Conjugated bilirubin
Normal
Unconjugated bilirubin
Urobilinogen
Decreased / Negative
Urine Color
Normal (urobilinogen)
Dark (urobilinogen + conjugated bilirubin)
Dark (conjugated bilirubin)
Stool Color
Pale
Alkaline phosphatase levels
Alanine transferase and Aspartate transferase levels
Conjugated Bilirubin in Urine
Not Present
Present

64. Unconjugated hyperbilirubinemia
Overproduction of bilirubin may occur with excess destruction of red cells, with ineffective erythropoiesis or with increased catabolism of heme compounds in the liver.
Hemolysis may be intravascular (heme in plasma), extravascular (in cells of the reticuloendothelial system) or a combination of both.

65. Hemolysis and ineffective erythropoiesis
are the only relevant causes of bilirubin overproduction in humans
Hemolysis, even if severe, usually results in mild hyperbilirubinemia (<5 mg/dL) unless there is coexistent liver disease, which may contribute to concomitant conjugated hyperbilirubinemia.
inherited disorders of the red cell membrane (sickle cell anemia)
inherited disorders of hemoglobin (thalassemia)
inherited disorders of red cell enzymes (glucose-6-phosphate dehydrogenase or pyruvate kinase deficiency)
acquired hemolytic conditions
hypothyroidism and hyperthyroidism
sepsis
drugs (e.g., isoniazid, a-methyldopa, phenothiazines, nonsteroidal antiinflammatory drugs, rifampicin, sulfonamides, thiazides, ribavirin)

66. Bilirubin uridine diphosphate glucuronosyltransferase deficiencies
disorders characterized by abnormalities of the bilirubin UGT enzyme UGT-1A1 and consequently are manifest by unconjugated hyperbilirubinemia.
Gilbert syndrome is common
the other disorders remain rare

67. Gilbert syndrome
unconjugated hyperbilirubinemia occurring in the absence of overt hemolysis or liver disease
Typically, there are mild, chronic or intermittent episodes of jaundice that increase with intercurrent illness, fasting, stress, fatigue, menses and ethanol and nicotinic acid intake.
Three to 8% of the population is affected, with a male predominance.
It is usually inherited in an autosomal recessive pattern and is rarely manifest before puberty.

68. Clinical findings
Patients are generally asymptomatic and nonspecific symptoms of fatigue and abdominal pain do not correlate with bilirubin levels.
Mildly lemon-tinged sclera are usually the only physical findings.

69. Laboratory
50% of patients - mild hemolytic anemia of uncertain origin.
serum bilirubin - usually higher than 3 mg/dL, may increase to 5 to 8 mg/dL during stress
other hepatic biochemical indices are normal

70. Diagnosis careful history and physical examination
provocative fasting studies to confirm the diagnosis
fasting serum bile acid levels are normal, in contrast to the hyperbilirubinemia of liver disease
bilirubin UGT activity is reduced to approximately one-fourth of normal
reduced bilirubin diesters and increased bilirubin monoglucuronides

71. Good prognosis routine use of liver biopsy is not indicated
Gilbert syndrome is a benign condition and no therapy is routinely required.

72. Crigler-Najjar syndrome
may occur from birth
Type I is a rare autosomal recessive disorder, characterized by a complete deficiency of the enzyme bilirubin UGT
Crigler-Najjar type I bile contains only traces of bile conjugates.
Heterozygotes have normal bilirubin levels.
Infants develop severe unconjugated hyperbilirubinemia within 7 days of birth, followed by kernicterus and bilirubin encephalopathy if prompt therapy is not initiated.
Death follows within 18 months if untreated.

73. Crigler-Najjar syndrome
Type II (Arias disease) is an autosomal dominant disorder with variable penetrance that results in various levels of unconjugated hyperbilirubinemia.
Type II is caused by a variety of mutations in exons 1A1, 2 and 5 of the UGT-1 gene locus
Affected persons have about 10% of normal bilirubin UGT activity.
Bilirubin monoconjugates and even some diconjugate are present in bile.
Jaundice often is not apparent until the second year of life.
Bilirubin levels rarely exceed 20 mg/dL.

75. Isolated unconjugated hyperbilirubinemia
differential diagnosis is limited
The critical determination is whether the patient is suffering from a hemolytic process resulting in an overproduction of bilirubin (hemolytic disorders and ineffective erythropoiesis) or from impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders).

77. Conjugated hyperbilirubinemia
defined by a conjugated bilirubin level greater than 30% of the total bilirubin level
congenital
familial
acquired

78. Congenital hyperbilirubinemias
Rotor syndrome
Dubin-Johnson syndrome
Familial cholestasis
Benign recurrent intrahepatic cholestasis
Choledochal cystic disorders
Hepatocellular diseases
Infiltrative disorders
Infection
Bone marrow transplantation
Total parenteral nutrition

79. Rotor syndrome rare, asymptomatic, benign
manifested as conjugated or mixed hyperbilirubinemia
autosomal recessive disorder that becomes apparent in childhood
total bilirubin levels are usually 2 to 5 mg/dL, which are greater than 50% conjugated bilirubin, with bilirubinuria and exacerbation of hyperbilirubinemia during illness.
other liver tests, including bile acids, are normal, as is liver histology
oral cholecystogram is normal
radionuclide scans show absent or markedly delayed excretion
it is unclear whether the primary defect is impaired secretion or impaired storage of bilirubin
urinary coproporphyrins are markedly increased, especially type I

80. Dubin-Johnson syndrome
autosomal recessive syndrome resulting in impaired ATP-mediated transport of bilirubin diglucuronide as well as other organic ions
total bilirubin levels are usually between 2 and 5 mg/dL
other liver tests are normal.
patients usually present after puberty and exacerbations occur during intercurrent illness and with some drugs
the secretory defect in patients with Dubin-Johnson syndrome results in abnormal radionuclide scans and oral cholecystographic studies
bile salt secretion is normal
total urinary coproporphyrin levels are normal
there is an increase in type I levels in the urine and a decrease in type III levels
liver histology reveals a darkly pigmented liver that is black on gross inspection

81. Familial cholestasis defect in the generation of bile flow
chronic persistent hepatocellular cholestasis usually leading to cirrhosis
exclusion of other metabolic and anatomic defects
autosomal recessive inheritance patterns
Clinically, the disease is characterized by jaundice, steatorrhea, growth retardation, hepatosplenomegaly and watery diarrhea.
Biochemically: bilirubin, alkaline phosphatase and serum bile acids are elevated, glutamyltransferase and biliary bile acid concentrations are low.

82. HEPATOCELLULAR CONDITIONS
viral hepatitis
drug or environmental toxicity
alcohol
end-stage cirrhosis from any cause
AST rarely exceeds 300 U/L.
The degree of aminotransferase elevation can occasionally help in differentiating between hepatocellular and cholestatic process. (While ALT and AST values less than 8 times normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in acute hepatocellular diseases. Patients with jaundice from cirrhosis can have normal or only slight elevations of the aminotransferases.)

83. APPROACH TO THE PATIENT WITH JAUNDICE
The investigation of a patient with jaundice begins with a thorough review of the history of presentation, medication use, past medical history, examination and evaluation of liver-related laboratory tests.
1. Is the elevated bilirubin conjugated or unconjugated? In general, most jaundiced patients will not have isolated unconjugated hyperbilirubinemia.
2. If the hyperbilirubinemia is unconjugated, is it caused by increased production, decreased uptake, or impaired conjugation?
3. If the hyperbilirubinemia is conjugated, is the problem intrahepatic or extrahepatic?
4. Is the process acute or chronic?

84. Diagnosis by age of the patient
In neonates, physiological jaundice is overwhelmingly the most common cause of jaundice, with biliary atresia, infections (TORCHES) and metabolic diseases together accounting for less than 25% of cases.
In adolescents, Gilbert syndrome and viral hepatitis account for 80% of cases, with the remainder including toxins, drugs and autoimmune and biliary tract diseases.
In young adults, viral hepatitis is the most common cause of jaundice, followed by biliary tract disease, alcoholic liver disease and autoimmune diseases, genetic diseases (hemochromatosis and Wilson disease).
In elderly patients, malignant disease accounts for half of the cases of jaundice. 10% of abnormal liver tests in hospitalized patients are associated with drug toxicity [whether hepatocellular (acetaminophen), cholestatic (anabolic steroids) or mixed (sulfonamides)]. Autoimmune disease has a second peak in the elderly.

85. Neonatal jaundice
Unconjugated hyperbilirubinaemia, often with mild clinical jaundice, occurs in all full-term newborn infants.
Bilirubin concentrations are maximal at 2 to 5 days after birth, but the plasma bilirubin rarely exceeds 90 μmol/l; neonatal jaundice is more severe in premature infants.
It is attributed to a combination of immaturity of hepatic glucuronyl transferase and the added load of bilirubin from rapid haemolysis of surplus fetal red blood cells in the neonatal period.
Before birth, fetal bilirubin is excreted by the mother and meconium as well as stools are pale because of the reduced excretion of bilirubin.
If haemolysis is increased, as in rhesus or other fetomaternal incompatibility of red cell antigens, causing haemolysis of fetal red blood cells by maternal antibodies, then severe jaundice and kernicterus can occur.

86. Neonatal jaundice
Acidosis and some drugs (sulphonamides, salicylates, penicillin) may increase kernicterus by displacing unconjugated bilirubin from albumin.
Glucose-6-phosphate deficiency can also cause jaundice and anaemia in the neonatal period
Neonatal infection, birth trauma and hypothyroidism may compound hyperbilirubinemia
Severe neonatal hyperbilirubinemia has neurotoxic sequelae in the form of bilirubin encephalopathy. Kernicterus describes the pathological findings of yellow staining and necrosis of neuronal cells of the basal ganglia, hippocampal cortex, and subthalamic area, and clinically, it may follow an acute or chronic course with potentially debilitating outcomes.

87. Postoperative jaundice
halothane hepatitis
post-transfusion viral hepatitis
incompatible blood transfusion
drugs
bile duct damage
cardiac surgery (may be due to reduced hepatic blood flow during surgery)
in intensive care units

88. Liver disease in pregnancy
includes disorders unique to pregnancy and those coincident with or exacerbated by pregnancy
Normal changes during pregnancy include a lower mean serum albumin (3.1 g/dL), resulting from hemodilution, and a higher alkaline phosphatase level (two to four times normal), mainly of placental origin. Fibrinogen, transferrin, and cholesterol levels are also increased. Serum aminotransferases, bilirubin, serum bile acids and glutamyltransferase levels are unchanged.
Spider angiomata and palmar erythema may be seen in more than 60% of pregnant women.
The differential diagnosis of hepatic disorders of pregnancy is dependent on the time of onset in relation to the stage of gestation and the type of symptoms and signs. Careful history of present and past pregnancies, as well as parity, including a family history of complicated pregnancies, may provide important clues to diagnosis.

89. Cholestasis of pregnancy
bilirubin and alkaline phosphatase levels rise during the third trimester and intolerable itching and frank jaundice develop, all of which rapidly remit after delivery
The severity of the syndrome increases in successive pregnancies.
The fetus is probably not affected, but premature induction of labour may be needed for the mother's sake.
The contraceptive pill frequently causes a milder syndrome in the same susceptible women.
Pregnancy, by affecting bilirubin excretion, may bring the jaundice of primary biliary cirrhosis or the Dubin–Johnson/Rotor syndromes to notice.

90. Cholestasis after liver transplantation
early, within 6 months of transplantation
late, after 6 months from transplantation
overlap may occur

91. Early cholestasis
may be related to the condition of the donor liver, vascular and biliary problems, infections, and acute rejection
Functional cholestasis related to donor liver preservation injury (cold or rewarming ischemia or reperfusion injury) peaks between 10 and 16 days postoperatively and usually resolves with supportive management.
Bacterial infection may result in cholestasis and mandates a systematic evaluation of potential sources, particularly the biliary tree. Cholestasis may result from viral infection, by cytomegalovirus, chiefly within 3 months of transplantation. Direct viral culture, the faster shell vial culture technique or histologicaldocumentation of the cytopathic effects and microabscesses may confirm the diagnosis.
The integrity of the bile ducts is dependent on the hepatic arterial supply. Subacute or incomplete hepatic arterial thrombosis can result in chronic ductal ischemia, bacteremia from cholangitis and ultimately nonanastomotic biliary strictures.

92. Late cholestasis
may result from chronic rejection, recurrent disease and bile duct damage.
Chronic rejection is characterized histologically by bile duct atrophy and loss leading to progressive cholestasis and graft failure that is unresponsive to antirejection therapy.
Primary biliary cirrhosis may recur in 17% of patients.
Fibrosing cholestatic hepatitis is an early aggressive posttransplantation form of recurrent viral hepatitis, especially hepatitis C. It rapidly leads to graft failure and is characterized histologically by intrahepatic cholestasis with perisinusoidal fibrosis and minimal inflammation. Retransplantation is often necessary.

93. DIAGNOSTIC APPROACH
algorithms useful in the differential diagnosis and evaluation of a patient with jaundice
phyisical examination
laboratory tests
non-invasive tests (US, CT, MRI, radionuclide imaging)
invasive tests (ERCP, PTC, EUS)
liver biopsy

95. Physical examination
examination for evidence of chronic liver disease and extrahepatic disease
Jaundice is differentiated from other abnormalities in skin color, such as hypercarotenemia, uremic pigmentation, picric acid ingestion or quinacrine therapy because only bilirubin stains the sclera, because of its high affinity for elastin.
Later and especially if the jaundice is severe, the skin color be greenish.

96. Physical examination
A shrunken, nodular liver may allow one to identify cirrhosis and a palpable mass may indicate an abscess or malignant tumor. If the liver span is greater than 15 cm, the physician should consider fatty infiltration, congestion, other infiltrative diseases or malignant disease.
Spider angiomata, palmar erythema and distended abdominal veins in a patient with jaundice indicate cirrhosis.
Ascites in the presence of jaundice usually indicates cirrhosis, although it can be seen with malignant disease and severe acute disease, such as viral or alcoholic hepatitis.
Splenomegaly may be seen in patients with infections, infiltrative diseases, viral hepatitis or cirrhosis.
A palpable, distended gallbladder suggests biliary obstruction, often malignant in origin.
Asterixis is an unusual finding, except in fulminant hepatic failure and end-stage liver disease.

97. Laboratory tests
total and direct bilirubin - Patients with unconjugated hyperbilirubinemia should be evaluated for evidence of hemolysis, which includes a reticulocyte count, examination of the peripheral smear, serum level of lactic dehydrogenase, and haptoglobin levels. An abnormality in any of these values may lead the clinician to look for evidence of ineffective erythropoiesis, such as vitamin B 12 deficiency, lead toxicity, thalassemia, or sideroblastic anemia. When hemolysis is excluded in patients with unconjugated hyperbilirubinemia, most asymptomatic healthy patients have Gilbert syndrome.
serum aminotransferases and alkaline phosphatase – can differentiate hepatocellular from cholestatic disease. Bilirubin levels consistently less than 5 mg/dL are not seen in obstruction, unless early, but they are common in patients with cirrhosis. Bilirubin levels greater than 20 mg/dL in the presence of normal renal function, especially in elderly patients, should make the clinician suspect malignant biliary obstruction.

98. Laboratory tests – second line
To evaluate the patient for evidence of obstruction and exclusion of bone disease (e.g., glutamyltransferase, 5'nucleotidase, leucine aminopeptidase), specific liver diseases (e.g., antimitochondrial antibody, hepatitis serologies, a 1-antitrypsin, iron levels, ceruloplasmin), malignant disease (e.g., a-fetoprotein) and autoimmune phenomena (e.g., immunoglobulins, sedimentation rate, antinuclear antibody).
Bile acids are increased in virtually all forms of hepatobiliary disease and are not usually useful in determining the cause of jaundice (except in inherited disorders of bilirubin metabolism, when they are normal).
Albumin levels and prothrombin time should be determined to assess liver function.
Protein levels help to differentiate acute from chronic liver disease. Elevated globulin with hypoalbuminemia supports the diagnosis of cirrhosis, as does failure of the prothrombin time to correct after oral or parenteral administration of vitamin K. A trial of vitamin K should be given and administered parenterally to ensure adequate absorption. Hypercholesterolemia is often seen in patients with cholestasis.

99. More laboratory …
Urine tests that signal cholestasis or elevated bilirubin include urinary urobilinogen and urinary conjugated bilirubin.
In acute hyperbilirubinemia, jaundice can lag behind bilirubinuria.
The renal threshold for conjugated bilirubin is 1 mg/dL, which is less than that needed to produce clinical jaundice. False-positive urine test results occur with salicylates, and phenothiazines and false-negative results occur if the urine is not analyzed promptly.
A positive urine test result is a sensitive indicator of conjugated hyperbilirubinemia and should prompt further investigation.

100. Ultrasound is the first test used to detect biliary obstruction
the diagnostic accuracy ranges from 77% to 94%
the result is most accurate when the bilirubin level exceeds 10 mg/dL
ultrasound allowed a correct diagnosis in 86% of icteric patients
sensitivity of up to 77% and specificity of 83% to 95% for bile duct obstruction

102. 84 year-old man presented with jaundice and epigastric pain
84 year-old man presented with jaundice and epigastric pain. Several biliary calculi are shown within the dilated distal common bile duct on this abdominal ultrasound.

103. CT imaging
has a sensitivity of 60% to 90% and results rely less on the operator’s proficiency
is not impeded by fat
is more expensive than ultrasound and requires intravenous contrast medium in many instances
unless the patient is obese, ultrasound should be the initial test of choice

104. Images in 52-year-old woman with jaundice, abdominal pai, and weight loss due to unresectable pancreatic cancer. (a) Transverse contrast-enhanced CT image shows hypoattenuating mass in the head of the pancreas (∗) abutting splenic vein (arrow). (b-d) Curved planar reformations (cpr) show mass adjacent to and deforming superior mesenteric vein (black arrows), inferior mesenteric vein (imv) (arrowheads), and splenic vein (white arrows).

105. Magnetic Resonance Imaging
is generally insufficiently sensitive or specific in the assessment of diffuse liver disease
is more sensitive and specific than CT with contrast for the detection and evaluation of focal and malignant lesions
The MRI characteristics of stationary and mobile liquids makes MR cholangiopancreatography (MRCP) and MR angiography powerful noninvasive diagnostic tools. Bile duct calculi are seen particularly well with MRCP. With MRI, imaging of the biliary tree is feasible both proximal and distal to the site of obstruction. This is particularly valuable after inadequate or unsuccessful endoscopic retrograde cholangiopancreatography (ERCP), although its use is more difficult to justify if there is a high probability of the need for therapeutic intervention.

106. A twenty six year old male patient presented to the surgical emergency with history of high-grade fever and right hypochondrial pain of one week duration. The patient was icteric and had a tender hepatomegaly.
MRI coronal section (T2W MRI) shows linear serpinginous shadows within the fluid filled cyst in the right upper lobe, suggestive of collapsed membranes (arrow). The dilated left main hepatic duct can be seen.

107. MRC scan the cyst can be seen to communicate with the common hepatic duct. The membranes can be seen entering the biliary duct
Hydatid serology was found to be positive.

108. Radiolabeled Technetium-Sulfur Colloid
Radionuclide imaging is an excellent means of detecting cystic duct obstruction.
It is the test of choice if acute cholecystitis with cystic duct obstruction and biliary leakage is suspected, but it has little value in differentiating intrahepatic from extrahepatic causes of cholestasis.
False-negative tests occur with prolonged fasting, TPN, and bilirubin levels greater than 5 mg/dL.

109. Biliary scintigraphy with technetium (a HIDA scan) is an excellent test to decide whether common bile duct and cystic ducts are patent.  This involves the administration of an isotope which concentrates within the gallbladder, and flows into the duodenum and biliary tree allowing visualization.

110. ERCP
ERCP can localize the site of obstruction in more than 90% of patients.
It is particularly helpful in diagnosing patients with common duct stones.
Because it has therapeutic capabilities, it allows some patients to avoid surgery.
The major reasons for nonvisualization of the biliary tree during ERCP are prior surgery (e.g., Roux-en-Y loop) and an inability to cannulate the sphincter of Oddi.
The morbidity rate is 2% to 3%, somewhat less than with PTC.
The most common complications are pancreatitis, bleeding and cholangitis.
The rate of sepsis is less than 1% if prophylactic antibiotics are given when an obstruction is suspected.

111. 89-year-old male patient presented with epigastric pain, low grade fever and vomiting. Lab showed anormal liver function including jaundice. ERCP revealed stress ulcers with bleeding, suppurative cholangitis and CBD stone.

112. Percutaneous transhepatic cholangiography
PTC visualizes the biliary tree in 90% to 100% of patients with dilated ducts and localizes the site of obstruction in 90% of cases.
To perform the test safely, PTC usually requires a prothrombin time of less than 16 seconds, a platelet count greater than 50,000 and the absence of ascites. Minor complications occur in 30% of patients.
Major complications, including sepsis, bleeding, biliary leak, pneumothorax, arteriovenous fistula, hematoma, abscess and peritonitis, occur in 1% to 10% of patients who undergo PTC.

113. 50-year-old woman with jaundice
50-year-old woman with jaundice. Percutaneous transhepatic cholangiogram shows large type 1 bile duct cyst of extrahepatic bile duct containing contrast material (arrows). Slightly distended left and right hepatic ducts are noted (open arrows). Percutaneous needle (Perc), gallbladder (GB), and duodenum (D) are noted.

114. Endoscopic ultrasound
EUS combines endoscopy with real-time, high-resolution ultrasound and provides excellent sonographic visualization of the biliary tree without bowel gas interference.
EUS is superior to ultrasound and CT for diagnosing bile duct stones.
EUS is comparably accurate but safer and less expensive than ERCP when evaluating patients with suspected choledocholithiasis.
If available, EUS should be considered, particularly if there is a contraindication to ERCP or if prior ERCP was unsuccessful.

115. endoscopic retrograde cholangiography

116. Liver biopsy
If high-grade extrahepatic obstruction has been excluded or hepatocellular disease is strongly suspected, a liver biopsy should be performed.
Liver biopsy can correct 20% of errors in clinical diagnosis.
In the workup of a patient with hyperbilirubinemia, a liver biopsy can be useful if other diagnostic tests are unrevealing. This diagnostic strategy is essential. If the ERCP result is nondiagnostic, a liver biopsy should be performed. 5% of the cases of extrahepatic cholestasis are diagnosed by liver biopsy because of inadequate clinical suspicion of obstruction or an inability to visualize the ducts adequately.
For 15% of cases, a liver biopsy is not helpful in determining the cause of the hyperbilirubinemia. If the clinician’s level of suspicion is high and the ultrasound scan is negative, a cholangiogram should be performed.

117. COMPLICATIONS OF CHOLESTASIS
Pruritus
Hepatic osteodistrophy
Fat-soluble vitamin deficiency - is common in patients with prolonged cholestasis

118. Pruritus
commonly associated with cholestasis and may limit activity, cause anxiety, disturb sleep patterns and result in secondary skin infection
the presence and severity of pruritus in cholestasis do not necessarily correlate with the degree of cholestasis
the pathogenesis of cholestasis-associated pruritus is uncertain
Formerly, proposed accumulated endogenous pruritogens of cholestasis interacting with cutaneous nerve endings were implicated.
More recently, the concept that pruritus is of central origin, mediated by endogenous opioid or serotonin ligands, has gained credence.

119. Hepatic osteodystrophy
metabolic bone disease that occurs in patients with chronic liver disease, particularly cholestatic disease
osteoporosis and osteomalacia
increased cytokine activation involving IL-1, IL-6 and tumor necrosis factor may be important in modifying osteoclast or osteoblast function
osteomalacia results from impaired bile salt–assisted intestinal absorption of ingested vitamin D and consequently calcium and phosphate and it is inversely associated with the degree of steatorrhea and cholestyramine use