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 20-30 years following the initial insult to the liver.

• 25% of patients have no history or risk factors for the development of cirrhosis.

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.

The relative frequency of various tumors of the liver

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

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.

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.

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.

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.

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.

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

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.

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.

Microscopic

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

Decompensation of cirrhosis

• ascites • refractory variceal bleedingthe diffuse infiltrating cancers further worsen

hepatic function, resulting in:• hyperbilirubinemia• coagulopathy • encephalopathy

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

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

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

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

Paraneoplastic phenomena- are rare

• hypercalcemia• erythrocytosis• hypoglycemia• thrombophlebitis migrans• arterial hypertension• the syndrome of watery diarrhea, hypokalemia and

achlorhydria

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.

Physical findings

• Jaundice• Ascites• Hepatomegaly• Alcoholic stigmata (Dupuytren contracture, spider

angiomata)• Asterixis• Pedal edema• Periumbilical collateral veins• Enlarged hemorrhoidal veins

Differential diagnosis

• Cholangiocarcinoma• Cirrhosis• Hepatocellular adenoma• Dysplastic nodules in cirrhosis• Fibrous nodular hyperplasia• Metastatic disease• Primary hepatic lymphoma• Hepatoblastoma• Hemangioma

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.

Results consistent with cirrhosis:

• total bilirubin• aspartate aminotransferase (AST)• alkaline phosphatase• albumin• prothrombin time

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.

Ultrasound examination of the liver

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.

Contrast-enhanced CT scan

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.

Imaging modalities in diagnosis of hepatocellular cancer

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.

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.

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.

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)

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.

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

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

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

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.

Complications

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

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.

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.

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.

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.

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.

Bilirubin metabolism

• Bilirubin is the end product of heme degradation.• Under normal circumstances, bilirubin is removed

from the circulation rapidly and efficiently by hepatocytes.

1. Hepatocellular uptake2. Intracellular binding3. Conjugation4. Biliary excretion

Pathophysiology

1. excess bilirubin formation2. altered uptake3. defective conjugation4. diminished excretion

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.

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.

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

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.

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.

Function test Pre-hepatic Jaundice Hepatic Jaundice Post-hepatic Jaundice

Total bilirubin Normal / Increased Increased

Conjugated bilirubin Normal Increased Increased

Unconjugated bilirubin Normal / Increased Increased Normal

Urobilinogen Normal / Increased Increased Decreased / Negative

Urine Color Normal (urobilinogen) Dark (urobilinogen + conjugated bilirubin) Dark (conjugated bilirubin)

Stool Color Normal Pale

Alkaline phosphatase levels

Normal

Increased

Alanine transferase and Aspartate transferase levels Increased

Conjugated Bilirubin in Urine Not Present Present

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.

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)

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

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.

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.

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

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

Good prognosis

• routine use of liver biopsy is not indicated

• Gilbert syndrome is a benign condition and no therapy is routinely required.

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.

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.

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).

Conjugated hyperbilirubinemia

• defined by a conjugated bilirubin level greater than 30% of the total bilirubin level

• congenital• familial• acquired

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

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

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

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.

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.)

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?

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.

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.

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.

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

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.

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.

Cholestasis after liver transplantation

• early, within 6 months of transplantation

• late, after 6 months from transplantation

• overlap may occur

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.

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.

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

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.

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.

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.

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.

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.

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

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.

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

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

endoscopic retrograde cholangiography

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.

COMPLICATIONS OF CHOLESTASIS

• Pruritus

• Hepatic osteodistrophy

• Fat-soluble vitamin deficiency - is common in patients with prolonged cholestasis

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.

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