Advanced Therapy in Gastroenterology and Liver Disease - part 9 potx

Some of these patients will already have the histologic features of PBC on liver biopsy, and at 10-year follow-up, the majority develop cholestasis, many with symptomatic disease.. It is

Drug-Induced Liver Disease / 693

carbonated soda or antiemetic medication A feeding tube

may be needed in patients who cannot tolerate the

med-ication orally Oral N-acetylcysteine has no serious side

effects, but the IV preparation may rarely cause an

ana-phylactic reaction

Other Therapies

Apart from N-acetylcysteine treatment for acetaminophen

poisoning, therapy for drug-induced liver injury is scant

A short course of high-dose corticosteroid may be used for

severe drug-induced liver disease, especially in patients with

systemic features of a hypersensitivity reaction However,

corticosteroids have not been proven to be of value in

con-trolled trials Nevertheless, we recommend a short course

of corticosteroids when systemic features of immune

hypersensitivity accompany acute hepatitis (eg, phenytoin

skin rash and liver injury) In patients with prolonged

drug-induced cholestatic liver disease, ursodeoxycholic acid

treatment may be of use, although the efficacy is unproved

Prevention

Because there is little specific therapy for drug-induced liver

disease, prevention is of great importance This process

starts during drug development It is important to

moni-tor for ALT abnormality, as well as signs and symptoms

of liver disease, during clinical studies with new drugs Even

after a drug receives approval from the US Food and Drug

Administration, surveillance and report of suspected cases

should continue to identify hepatotoxicity that may not

have been apparent during the initial clinical studies

For patients who take drugs that are known to have

hepa-totoxic potential, monitoring liver enzymes should be

consid-ered Careful follow-up may identify emerging hepatotoxicity

and, thus, prevent severe drug-induced liver disease However,

this approach is most rational for delayed-onset, idiosyncratic,

drug-induced liver disease.When starting any drug, all patients

should be educated about the signs and symptoms of liver

dis-ease and urged to report such symptoms to health care

pro-fessionals immediately This practice is particularly important

for patients who take multiple medications because immune

cross-sensitization has been known to occur among drugs in

the same class, such as anticonvulsants, macrolides, or

phe-nothiazines If patients have a history of an immune

hyper-sensitivity reaction to one drug, they may need to avoid other

drugs from the same class

Supplemental Reading

Ballet F Hepatotoxicity in drug development: detection, significance and solutions J Hepatol 1997;26 Suppl 2:26–36 Danan G, Benichou C Causality assessment of adverse reactions

to drugs—I A novel method based on the conclusions of international consensus meetings: application to drug- induced liver injuries J Clin Epidemiol 1993;46:1323–30 Degott C, Feldmann G, Larrey D, et al Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia Hepatolog y 1992;17:244–51.

Farrell G Liver disease caused by drugs, anesthetics, and toxins In: Feldman M, Friedman LS, Sleisenger MH, editors Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis, and management 7th ed Philadelphia: Saunders; 2002.

Kaplowitz N Drug-induced liver disorders: implications for drug development and regulation Drug Saf 2001;24:483–90 Kaplow itz N, Aw TY, Simon FR, Stolz A Drug-induced hepatotoxicity Ann Intern Med 1986;104:826–39.

Ke ays R , Ha r r i s on P M , Wen don JA , e t a l In t r aven o u s acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial BMJ 1991;303:1026–9 Liu ZX, Kaplowitz N Immune-mediated drug-induced liver disease Clin Liver Dis 2002;6:755–74.

Makin AJ, Wendon J, Williams R A seven year experience of severe acetaminophen-induced hepatotoxicity (1987–1993) Gastroenterology 1995;109:1907–16.

O’Grady J Paracetamol-induced acute liver failure: prevention and management J Hepatol 1997;26 Suppl 1:41–6.

Ostapowicz G, Fontana RJ, Schiodt FV, et al Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Ann Intern Med 2002;137:947–54 Schiødt FV, Rohling FA, Casey DL, Lee WM Acetaminophen toxicity in an urban county hospital N Engl J Med 1997; 337:1112–7.

Seeff LB, Cuccherini BA, Zimmerman HJ, et al Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure Ann Intern Med 1986;104:399–404.

Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH Efficacy of oral

N-acetylcysteine in the treatment of acetaminophen overdose.

N Engl J Med 1988;319:1557–62.

Stieger B, Fattinger K, Madon J, et al Drug- and induced cholestasis through inhibition of the hepatocellular bile salt export pump (BSEP) of rat liver Gastroenterology 2000;118:422–30.

CHAPTER 120

Liver Disease During Pregnancy

Cholelithiasis and gallstone disease are seen in 3 to 12% ofpregnant women, with higher incidence in the second andthird trimesters Most women are asymptomatic, however,

up to 50% will have recurrent pain and worsening toms as pregnancy advances Asymptomatic cholelithiasisrequires no treatment Symptomatic disease should initially

symp-be managed conservatively, but up to 35% will fail tion management and require surgical intervention If pos-sible surgery should be delayed until the second trimester.Likewise, medical management during the third trimester ispreferable with surgical intervention following delivery.Variable outcomes are seen in pregnant women withcirrhosis and portal hypertension Significant hepaticdecompensation (jaundice, ascites, and encephalopathy)can occur Preexisting portal hypertension may be wors-ened by increased total blood volume, possibly increasingthe risk of bleeding from esophageal varices Pregnancy isgenerally uneventful in patients with chronic hepatitis B

medica-or C virus infections Women with autoimmune hepatitishave had successful pregnancies and should continue to be

treated with corticosteroids and/or azathioprine Women

with untreated Wilson’s disease are generally anovulatory,but can undergo successful pregnancy with following cop-

per chelation treatment Penicillamine or trientine therapy

Normal pregnancy induces physiologic, hormonal, and

bio-chemical changes which are adaptive and do not represent

significant pathology These changes may cause confusion

about the true status of the liver and the presence or absence

of disease Liver test abnormalities are seen in about 10%

of all pregnancies and represent disorders commonly seen

in the nongravid state (ie, viral hepatitis), disorders related

to pregnancy, or disorders unique to pregnancy

Normal Changes during Pregnancy

Anatomic Changes

The enlarging uterus rotates the liver superiorly and

pos-teriorly, however, the liver’s size and gross appearance do

not change Nonspecific histologic changes include

hepa-tocyte variability, cytoplasmic granularity, centrilobular fat

vacuoles, and a minimal increase in Kupffer cells Despite

increases in global maternal blood volume of 20 to 70%,

and a 30 to 50% increase in maternal cardiac output, liver

blood flow remains unchanged

Laboratory Studies

The major liver test changes during pregnancy are outlined

in Table 120-1 Increases in alkaline phosphatase levels

rep-resent an influx of the placental isoenzyme Decreases in

serum γ-glutamyl transpeptidase (GGT) are secondary to

impaired hepatic release Maternal hemodilution and

decreased hepatic synthesis lead to a relative decrease in

serum albumin Decreased hepatic synthesis of

antithrom-bin III and increased synthesis of fibrinogen lead to the

prothrombotic state seen in pregnancy There is a marked

increased hepatic synthesis of lipoproteins, cholesterol, and

triglycerides Increased concentrations of cholesterol found

in the bile

Physical Examination

Spider angiomata occur in 60 to 70% of women, with

pal-mar erythema in as many as 63% of white women and 39%

of black women These changes are likely due to the

hyper-estrogenemia seen during pregnancy and disappear in the

majority of women by about 7 weeks postpartum The liver

is normally not palpable

TABLE 120-1 Normal Changes During Pregnancy

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = γ -glutamyl tidase.

transpep-Liver Disease and Pregnancy / 695

should be continued in this setting because

discontinua-tion can lead to fulminant liver failure (the potential effects

of these medications on the fetus should be discussed with

the patient) Alcoholic women with significant liver disease

may be anovulatory and thus infertile

Pregnancy-Associated Liver Disorders

Hyperemesis Gravidarum

Nausea and vomiting occur in up to 90% of all

pregnan-cies Hyperemesis gravidarum (HG) has a prevalence of

0.35 to 1%, and is characterized by severe, persistent

nau-sea and vomiting during the first trimester Intractable

vomiting requires aggressive support, including, at times,

parenteral nutrition Risk associations include increased

body weight, multiple gestations, hyperemesis in a prior

pregnancy, and nulliparity

Up to half of women hospitalized for HG have liver

enzyme abnormalities, generally occurring within the first

1 to 3 weeks following onset of vomiting Aminotransferase

levels may be as high as 2 to 3 times normal, but rarely

above 1000 IU/L The more severe the vomiting, the higher

the elevation Mild elevations in bilirubin (rarely above

4 mg/dL) and jaundice, occasionally with pruritus, occur

Alkaline phosphatase levels are usually elevated beyondthose seen with normal pregnancy

The etiology of the hepatic abnormalities is unknown,but it is a relatively benign process Liver abnormalitiesresolve rapidly with resolution of emesis HG was at onetime a lethal disease, however, with early diagnosis andaggressive support, both maternal and fetal mortality isnow negligible

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (IHCP) is heralded bythe development of pruritus, liver enzyme abnormalities,and occasionally jaundice Most cases occur within the thirdtrimester of pregnancy (Table 120-2) The worldwide inci-dence varies; ICHP occurs in less than 1 to 2% of all preg-nancies in the United States, Asia, Australia, and Europe, but

in Bolivia, Chile, and Scandinavia, the incidence is as high

as 14%, with rates of 24% in the Araucanian Indians ofChile There is a greater prevalence among woman from theIndian subcontinent and the disease is rare in black patients.IHCP recurs in 60 to 70% of subsequent pregnancies and

is 5 times more frequent in women with multiple gestation.The etiology of ICHP is uncertain and is probably mul-tifactorial Seasonal variations suggest environmental influ-

TABLE 120-2 Features of Liver Disease of Pregnancy

trimester

Adapted from Larson AM Liver disease in pregnancy Clin Perspectives Gastroenterol 2001; 4:351(17).

AFLP = acute fatty liver of pregnancy; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HELLP = hemolysis, vated liver enzymes, and low platelets syndrome; ICPH = intrahepatic cholestasis of pregnancy; PT = prothrombin time.

ele-696 / Advanced Therapy in Gastroenterology and Liver Disease

ences Genetic components are suggested given that female

relatives of patients with IHCP often develop IHCP and

it is seen in successive generations (30 to 50% report a

pos-itive family history) Further support for this is the high

recurrence rate in subsequent pregnancies Nearly half of

the women who develop IHCP will also develop jaundice

when using oral contraceptives, suggesting that the genetic

defect is in estrogen processing

Estrogen concentrations peak in the third trimester of

pregnancy, perhaps explaining the onset of illness during

this time Serum bile acids are also markedly increased (10

to 100 times normal), suggesting decreased hepatic

capac-ity to either process or transport them Both estrogens and

monohydroxy bile acids are conjugated within the liver It

has been postulated that a genetic defect in sulfotransferase

activity leads to the accumulation of toxic metabolites via

glucuronidation Mutations have been described in the

MDR3 gene, which encodes for a biliary canalicular

phos-pholipid translocater MDR3 has been associated with

familial forms of intrahepatic cholestasis and in women

with IHCP associated with an elevated GGT Exogenous

progesterone administration or impaired secretion of

prog-esterone metabolites has also been implicated as a trigger

for IHCP in predisposed women

Nearly all affected women report intense pruritus, which

typically involves the palms and soles, but may be diffuse

Pruritus is often worse at night and becomes progressively

severe as the pregnancy progresses It may precede

abnormal-ities in liver tests There appears to be no correlation between

serum levels of bile acids and the severity of pruritus

Pruritus gravidarum, clinical jaundice within 1 to 4 weeks

after onset of pruritus, develops in 10 to 60% of patients

The skin appears normal but patients may have excoriations

secondary to scratching Systemic symptoms are generally

mild (see Table 120-2) Elevation in bilirubin correlates with

jaundice and is rarely greater than 5 to 6 mg/dL GGT

lev-els are normal to minimally elevated Prolonged

pro-thrombin time (PT) generally reflects the vitamin K

deficiency resulting from impaired bile salt formation

Serum bile acids are often as high as 100 times normal (bile

acid concentrations change little during normal pregnancy)

and are the most sensitive marker for IHCP They may be

the only abnormality, however, absolute levels do not

cor-relate with maternal symptoms, other liver tests, or with

prognosis

Diagnosis is made clinically, based upon history,

symp-toms, and laboratory studies Other causes of liver disease,

such as viral hepatitis or gallstone disease, must be ruled

out Liver biopsy is rarely needed and histopathology

reveals normal portal tracts, and bland cholestasis, with

bile plugs predominating in zone 3

Maternal management of IHCP is symptomatic and the

most common approach is early delivery (generally 37 to

38 weeks) Oral vitamin K should be started at the time of

diagnosis and, when given before delivery, can minimizepostpartum hemorrhage Treating pruritus is more prob-

lematic Antihistamines and benzodiazepines have been used with little success Studies using phenobarbitol have been

contradictory and it may cause neonatal respiratory

depression Dexamethasone (12 mg/d for 7 days with 3 day

taper) has been shown to improve pruritus Controlled als have not been done, however, and there is a report of

tri-worsened liver function with dexamethasone use Studies with S-adenosyl-methionine have shown conflicting results.

In two randomized controlled trials, it significantlydecreased pruritus (800 mg/d intravenously or 1,600 mg/dorally) In a third double blind randomized controlled trial,

no improvement was seen Pruritus has been successfully

treated with cholestyramine at 8 to 16 g per day, although

it is usually poorly tolerated It must be used with caution

as it may worsen maternal absorption of Vitamin K and

maternal steatorrhea

Therapy with ursodeoxycholic acid (UDCA) at dosages of

15 mg/kg/d leads to a reduction in pruritus, a reduction inmaternal serum bile acids and maternal aminotransferases,

and a reduction in delivery of bile acids to the fetus UDCA

also appears to decrease negative maternal and fetal

seque-lae UDCA can cross the placenta, but there have been no reports of fetal toxicity Because UDCA appears safe to

mother and fetus, it is reasonable to consider its use, keeping

in mind that it is not approved for this indication in theUnited States Larger randomized controlled trials are needed.Maternal prognosis is excellent with IHCP and there areusually no hepatic sequelae Symptoms progress until deliv-ery and then promptly disappear Jaundice resolves rapidlyand serum laboratory tests resolve over weeks to months.Acute liver failure does not occur IHCP is associated with

an increased incidence of primary postpartum hemorrhage(20 to 22%), likely due to vitamin K deficiency The inci-dence of cholelithiasis is also increased

Fetal prognosis is less benign Fetal morbidity and tality are significantly increased Premature labor (6 to60%), meconium-stained amniotic fluid (26 to 58%), fetaldistress (17 to 22%), and stillbirth (1 to 3%) are all seen.Early reports of fetal mortality were as high as 10 to 15%;however, with more aggressive management, this isimproving (1.7 to 3.5%) Unfortunately, there are noantepartum tests, which predict fetal compromise

mor-Acute Fatty Liver of Pregnancy

Acute fatty liver of pregnancy (AFLP) was first described

in 1934 and is a rare, idiopathic, potentially fatal diseasepresenting in the third trimester of pregnancy Incidenceranges from 1 of 7,000 to 1 of 16,000 deliveries and it con-stitutions 16 to 43% of severe liver disease seen duringpregnancy In its most severe form, it is manifest by ful-minant hepatic failure Seen worldwide, there appears to

be no ethnic or geographic variation

Liver biopsy provides the diagnostic gold standard, but

it is problematic if coagulopathy is present, and is rarelyneeded (Figure 120-1) Fatty changes in pancreatic acinarcells and renal tubular epithelia have also been describedand likely account for the findings of renal failure and pan-creatitis in these patients

Upper gastrointestinal hemorrhage (in 30 to 40% ofcases) occurs from a variety of causes Renal dysfunction

is generally mild to moderate, but 25% of patients developsevere renal failure and may require dialysis Coagulopathy(elevated PT), decreased antithrombin III levels, andthrombocytopenia) probably represents both hepatic syn-thetic dysfunction and peripheral consumption Frank dis-seminated intravascular coagulation (DIC) is common (up

to 70%) Pancreatitis develops in up to 30% of patients.Severe hypoglycemia may be seen in 25 to 50% of patientsand can occur at any stage in the disease

AFLP is a medical and obstetrical emergency It is oftendifficult to distinguish from toxic or viral hepatitis Patientsmay progress to fulminant liver failure and death or requireliver transplantation No specific therapy is available.Patients should promptly be admitted to an experiencedliver failure unit, since it is impossible to predict whichpatients will progress to liver failure The patient should bemedically stabilized and delivery attempted as soon as rea-sonably possible; ALFP never resolves before delivery.Aggressive maternal supportive care is required and freshfrozen plasma or cryoprecipitate may be necessary prior todelivery Blood glucose levels should be followed frequently.Likewise, PT must frequently be checked as this helps toassess the severity of disease With early diagnosis and man-agement, severity of disease and need for liver transplan-tation can be minimized

Maternal mortality has been reported as high as 70%,but can be improved to 10 to 20% with early delivery andintensive clinical support Fetal death occurs in 42 to 90%

FIGURE 120-1 Acute fatty liver of pregnancy The zone 3

cen-trilobular hepatocytes are swollen with microvesicular fat globules Sinusoidal compression can be seen but signs of hepatic necrosis and inflammation are often subtle Hepatic necrosis is a minor feature Courtesy of Carolyn A Riely, MD.

Liver Disease and Pregnancy / 697

The average maternal age at onset is 26 years (range, 16

to 39 years) with gestational age of onset at about 36 weeks

(range, 22 to 40 weeks) AFLP can rarely occur earlier in

pregnancy or shortly postpartum Primagravidas with male

gestations comprise most cases (see Table 120-2)

Recurrence with subsequent pregnancies, once thought to

be uncommon, is increasingly being reported

AFLP has little or no association with the hormonal

changes of pregnancy Its etiology is unknown, but may

stem from decreases in fetal mitochondrial fatty acid β

-oxidation by the enzyme long-chain 3-hydroxyacyl-CoA

dehydrogenase (LCHAD) Cholestatic liver disease with

microvesicular steatosis is often seen in patients with

LCHAD deficiency and an association between LCHAD

and AFLP has been described In many cases, the defect

appears to reside in the α-subunit of a trifunctional

pro-tein gene, which includes LCHAD activity This may lead

to poor fetal processing of triglycerides and free fatty acids,

which are toxic to the maternal hepatocytes Testing for the

genetic variants of the LCHAD enzyme is available When

the deficiency is present, recurrent disease can be seen in

subsequent pregnancies Not all investigations have

con-firmed this specific association and other genetic variants,

such as a defect in short-chain acyl-coenzyme A

dehydro-genase, have been associated with AFLP

Asymptomatic elevations in liver tests may be the only

abnormality, but the majority of severe cases present with

malaise, fatigue, anorexia, headache, nausea, and vomiting

(see Table 120-2) Right upper quadrant or epigastric pain

may mimic acute cholecystitis or reflux esophagitis Within

1 to 2 weeks of onset of symptoms, and within days

fol-lowing clinical jaundice, the disease may rapidly worsen,

leading to acute liver failure, with hepatic encephalopathy,

ascites, edema, and renal insufficiency Hallmarks of

preeclampsia (hypertension, proteinuria) are seen in over

50% of cases

Serum aminotransferases are generally less than

1,000 IU/L and do not reflect severity of liver dysfunction

Hyperbilirubinemia averages 10 to 15 mg/dL, but levels up

to 30 to 40 mg/dL have been reported In the setting of

eclampsia and preeclampsia, hyperbilirubinemia is

pre-dominantly unconjugated and hemolysis is present

Increases in alkaline phosphatase are difficult to interpret

because they overlap the normal values seen late in

preg-nancy A left-shifted leukocytosis and some degree of

thrombocytopenia are nearly universal

Clinical and laboratory findings suggest the diagnosis

of AFLP The differential diagnosis includes acute viral

hepatitis, acute toxic or drug-induced hepatitis,

preeclampsia-related liver disease (including hemolysis,

elevated liver enzymes, and low platelets syndrome

[HELLP]), and biliary tract disorders Imaging studies are

useful in assessing the biliary tree Virologic markers and

history can help to rule out viral and toxic hepatitis

698 / Advanced Therapy in Gastroenterology and Liver Disease

of cases with only minimal improvement with early

deliv-ery (36%) After delivdeliv-ery, affected women improve slowly;

full recovery often takes up to a month There are no

hepatic sequelae Infants who survive should be tested for

LCHAD deficiency and other fatty acid transport and

mito-chondrial oxidation disorders

Toxemia and Preeclampsia/Eclampsia

Pregnancy-induced hypertension (toxemia) is seen late in

pregnancy and remains a major medical challenge Five

to 10% of pregnant women with toxemia may develop

preeclampsia (hypertension plus proteinuria and

nonde-pendent edema) Preeclampsia generally occurs during the

second and third trimesters, and is most frequent in young

primagravidas Risk factors associated with preeclampsia

include nulliparity, a positive family history,

preeclamp-sia in a prior pregnancy, obesity, chronic hypertension or

renal disease, diabetes mellitus, a multiple gestation

preg-nancy, low socioeconomic status, and cigarette smoking

The cause of preeclampsia is unknown Laboratory

abnormalities are nonspecific Hepatic involvement is seen

in 10 to 30% of women with preeclampsia Mild elevations

of serum transaminases and, rarely, an increase in indirect

bilirubin can be seen in the absence of HELLP syndrome

Histologically, periportal fibrin deposition and hemorrhage

with hepatocellular necrosis are seen (Figure 120-2)

Preeclampsia can also have a similar histological pattern to

AFLP (both may develop microvesicular steatosis)

The clinical course may be mild or rapidly progressive

Onset of seizures signals development of true eclampsia

(usually young primagravidas), accounting for

approxi-mately 8% of all maternal deaths Control of the

hyper-tension is associated with reduced morbidity and mortality

in both the mother and the fetus Definitive therapy

requires delivery

HELLP Syndrome

The HELLP syndrome is a severe, life-threatening form

of preeclampsia reported as early as 1922 The acronym

HELLP was coined by Weinstein in 1982 to describe

preeclampsia associated with microthrombi,

thrombo-cytopenia, and coagulopathy HELLP syndrome has an

incidence of 0.11 to 0.85% of all live births and occurs in

20 to 25% of women with preeclampsia Ethnic variations

exist; risk is higher in white and Chinese populations

(rel-ative risk of 2.2) when compared to East Indian

popula-tions and is higher in black Americans when compared

to white Americans Patients are usually young

prima-gravidas (see Table 120-2)

The pathophysiology of preeclampsia and HELLP

syn-drome are unknown They may represent a single disease

spectrum, with the HELLP syndrome the most severe form

of preeclampsia An imbalance between endothelial

vasodi-latative (ie, nitric oxide) and vasoconstrictive (ie, lin) substances probably occurs and increased vascular toneleads to increased platelet adhesion and aggregation.Thrombin-induced activation of intravascular coagulationsubsequently occurs and can rapidly progress to disseminatedintravascular coagulation (DIC ~20%) The resultant severecoagulopathy leads to fatal hemorrhagic complications andmultiorgan failure These changes may be more common inpreeclampsia than in HELLP syndrome

endothe-Clinically, onset may be without warning Nonspecificsymptoms of nausea, vomiting, and malaise are seen in up

to 90% of women (see Table 120-2) Abdominal pain precedesbiochemical abnormalities in as many as 20 to 40% and visualchanges (15 to 30%) have been reported Hypertension may

be absent in as many as 20% of cases and 5 to 15% of patientshave little to no proteinuria Thus, about 15 to 20% of womenpresenting with HELLP syndrome have no signs ofpreeclampsia HELLP syndrome also appears to be associatedwith eclampsia, although reports of incidence are conflicting.Generalized edema (50 to 77% of cases) and development ofascites (8 to 10% of cases) carries an increased risk of con-gestive heart failure and adult respiratory distress syndrome.Pulmonary edema (6%) and acute renal failure may developand, in association with ascites, often coexist with DIC.Transient nephrogenic diabetes insipidus has been reported.Gestational thrombocytopenia is seen in 4 to 8% ofuncomplicated pregnancies, whereas thrombocytopenia inpreeclampsia ranges from 15 to 50% Those who developgestational thrombocytopenia are sevenfold more likely todevelop HELLP Platelet levels in HELLP syndrome are fre-quently less than 100,000/µL, and there is a positive corre-lation between the extent of platelet decline and the severity

of liver abnormalities Elevations of serum aminotransferases

FIGURE 120-2 Eclampsia/ hemolysis, elevated liver enzymes, and

low platelets syndrome (HELLP) Periportal fibrin deposition, hemorrhage, and hepatocellular necrosis seen in severe eclampsia The classic his- tologic picture of HELLP is one of periportal or focal parenchymal necro- sis, hyaline deposits, and vascular microthrombi In some cases, fibrin exudate has been reported similar to that seen in eclampsia Courtesy

of Carolyn A Riely, MD.

prolonging the gestation Optimal dosages for maternal

ther-apy have yet to be determined In one trial, intravenous

dex-amethasone (10 mg twice daily) was superior to

intramuscular betamethasone (12 mg once daily) in the

sta-bilization of maternal blood pressure, urinary output, andliver studies This group recommended initiation of treat-ment in all patients with Class 1 and 2 HELLP (see Table120-3), with discontinuation upon resolution of symptoms

Corticosteroids given postpartum have also been shown to

accelerate maternal recovery and lower maternal morbidity.Laboratory studies may actually worsen after delivery.Haptoglobin and LDH levels generally normalize within

24 to 48 hours postpartum Liver enzymes return to mal within 3 to 5 days Platelets begin to recover within 23

nor-to 29 hours postpartum, with normalization within 6 nor-to 11days Failure of the platelets to recover within the first 96hours postpartum is an indication of a severe decliningpostpartum course Plasamapheresis may be needed in thissetting, however, it’s use remains controversial

Hepatic infarction is usually associated severe right upperquadrant pain, fever, and significantly elevated serumaminotransferases (1,000 IU/L or higher) Hepatic infarc-tion and unruptured hepatic hematoma can be managedexpectantly and generally resolve without sequelae Hepaticrupture may develop in a small percentage of women (~1%)leading to massive hemoperitoneum and shock requiringearly intervention by a skilled surgeon and may be an indi-cation for liver transplantation HELLP syndrome may lead

to fulminant hepatic failure, requiring intensive care agement at a specialized liver failure unit Those patients whosurvive generally have no hepatic sequelae

man-Overall, maternal mortality may be as high as 8%.Maternal outcome following hepatic infarction is gener-ally favorable When hepatic hematoma with ruptureoccurs, it is responsible for maternal mortality of up to 50%and fetal mortality of 60 to 70% The risk of recurrentHELLP is about 2 to 37%, but has been reported to be ashigh as 61% if the prior pregnancy ended before 32 weeks.Fetal mortality is high (8 to 37%) and is associated withplacental insufficiency, fetal hypoxia, and intrauterine

Table 120-3 Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome Classification Systems

Incomplete Syndrome any one or two of the above

ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase.

Liver Disease and Pregnancy / 699

precede platelet drop off in HELLP syndrome Leukocytosis

also correlates with the severity of disease

Measurement of serum haptoglobin is the most

sensi-tive measure of hemolysis and it will be significantly

reduced in 95 to 97% of cases Elevations in serum

biliru-bin do not occur in all patients and are therefore a less

reli-able measure of hemolysis (see Treli-able 120-2) Other less

specific measures include schistocytes and burr cells on

peripheral blood smear (54 to 86%) and elevated serum

lactate dehydrogenase levels

The definitive diagnosis of HELLP syndrome requires

clin-ical suspicion as well as timely and appropriate laboratory

screening The differential diagnosis includes other causes of

hematologic and/or liver abnormalities, such as AFLP,

appen-dicitis, viral hepatitis, gallbladder disease, gastroenteritis, ulcer

disease, idiopathic thrombocytopenia purpura,

hemolytic-uremic syndrome, or thrombotic thrombocytopenic purpura

Microangiopathic hemolytic anemia, thrombocytopenia, and

elevated serum aminotransferase activity are essentially always

seen in the HELLP syndrome Liver biopsy is rarely needed to

establish the diagnosis, and women with the HELLP

syn-drome may not have evidence of hepatic synthetic

dysfunc-tion (see Figure 120-2)

The clinical course of HELLP syndrome is unpredictable

Maternal complications occur in up to 65% of cases,

includ-ing DIC (4 to 38%), placental abruption (10 to 16%), acute

renal failure (1 to 8%), severe ascites (5 to 8%), pulmonary

edema (2 to 10%), cerebral edema (1%), adult respiratory

distress syndrome (ARDS, 1%), and hepatic infarction or

rupture (1%) Eclampsia with maternal seizures can be seen

Events associated with maternal death include cerebral

orrhage, cardiopulmonary arrest, DIC, ARDS, hepatic

hem-orrhage, and hypoxic ischemic encephalopathy

Several authors have attempted to define and classify

HELLP syndrome based upon laboratory parameters

(Table 120-3) These classifications have been used to

pre-dict the rapidity of recovery, risk of recurrence, perinatal

outcome, and need for plasmapheresis

Intensive care in a tertiary care setting if appropriate

remains critical to the management of HELLP syndrome

Medical stabilization and careful maternal monitoring are

cru-cial Ultimately, prolongation of the pregnancy would improve

fetal outcome Complete bed rest is indicated and complete

reversal of symptoms with conservative treatment has been

reported in individual cases The development of DIC requires

immediate delivery following correction of coagulopathy

Aggressive treatment of severe hypertension and antiseizure

prophylaxis with magnesium sulfate are indicated It may not

be possible to prolong the pregnancy, and immediate

deliv-ery may be necessary The baby should be delivered in an

obstetric intensive care unit (fetal management is beyond the

scope of this chapter and will not be discussed)

Corticosteroids have shown significant benefit in

stabi-lizing maternal status, inducing fetal lung maturation, and

700 / Advanced Therapy in Gastroenterology and Liver Disease

growth restriction Prematurity at delivery also complicates

fetal survival In babies who survive, outcome is similar

to children of similar gestational age

Summary

Pregnancy-induced liver diseases carry a significant

mor-bidity and mortality for both mother and fetus Fortunately,

with early recognition and aggressive management, survival

rates have improved A multidisciplinary approach and high

level intensive care are crucial to enhanced patient outcome

Supplemental Reading

Abell TL, Riely CA Hyperemesis gravidarum Gastroenterol Clin

North Am 1992;21:835–9.

Audibert F, Friedman SA, Frangieh AY, Sibai BM Clinical utility

of strict diagnostic criteria for the HELLP (hemolysis,

ele-vated liver enzymes, and low platelets) syndrome Am J Obstet

Gynecol 1996;175:460–4.

Bacq Y Acute fatty liver of pregnancy Semin Perinatol 1998;

22:134–40.

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pregnancy: a prospective study of 103 pregnant women and

103 matched controls Hepatology 1996;23:1030–4.

Goodwin TM Nausea and vomiting of pregnancy: an obstetric drome Am J Obstet Gynecol 2002;185(5 Suppl Understanding): S184-9.

syn-Ibdah JA, Yang Z, Bennett MJ Liver disease in pregnancy and fetal fatty acid oxidation defects Mol Genet Metab 2000;71:182–9 Kenyon AP, Piercy CN, Girling J, et al Obstetric cholestasis, out- come with active management: a series of 70 cases BJOG 2002;109:282–8.

Lammert F, Marschall HU, Matern S Intrahepatic cholestasis of pregnancy Curr Treat Options Gastroenterol 2003;6:123–32 Magann EF, Martin JN Jr Twelve steps to optimal management

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Reyes H Acute fatty liver of pregnancy: a cryptic disease ening mother and child Clinics in Liver Disease 1999;3:69–81 Tsang IS, Katz VL, Wells SD Maternal and fetal outcomes in hyper- emesis gravidarum Int J Gynaecol Obstet 1996;55:231–5 Yates MR, Baron TH Biliary tract disease in pregnancy Clin Liver Dis 1999;3:131–46.

CHAPTER 121

that the disease progresses steadily from early stage to rhosis (about one stage per 2 years), this is not the casefor all patients In fact, there is evidence that sampling error

cir-is common in PBC Early-stage lesions may be seen in onepart of a biopsy, whereas fibrosis and/or cirrhosis are noted

in other areas of the same specimen That being said, inpatients with preserved liver synthetic function (normalalbumin, normal international normalized ratio, noascites), aside from liver biopsy, there is no other means toprognosticate Early-stage disease on biopsy, with adequatecore size, is still predictive of a better outcome than thefinding of significant fibrosis or cirrhosis In addition,recent data suggest that the presence of a lymphoplasma-cytic interface hepatitis portends rapidly progressive dis-ease, and more rapidly progressive bile duct loss has beenreported to precipitate liver failure even in the absence ofcirrhosis Therefore, we tend to biopsy patients at diag-nosis largely for prognostic reasons unless they are over theage of 70 years or have significant other comorbid illnesses,making it unlikely that PBC will alter their life expectancy.Naturally, in cases in which the diagnosis is not crystal clear,

a biopsy is imperative to confirm features typical of PBC

Some Caveats

Along with AMAs, patients will typically have evidence ofanicteric cholestasis with mild elevation of the serumaminotransferases on routine liver biochemistry Aspartateaminotransferase and alanine aminotransferase greaterthan four- to five-fold normal should prompt considera-tion of an alternative or concomitant diagnosis Similarly,patients who present with jaundice that subsequentlyresolves spontaneously are unlikely to have PBC In suchpatients, investigations to exclude biliary obstruction, drug

or alcohol toxicity, and viral hepatitis must be carried out

A small proportion of patients with PBC will also have dence of autoimmune hepatitis (AIH)—so-called PBC-AIH overlap syndrome Identification of such individuals

evi-is important because it may affect clinical management.Although no specific diagnostic criteria have been estab-lished for overlap syndrome, other suggestive featuresinclude IgG elevation (>2×upper limit of normal ), pos-itive smooth muscle and/or antinuclear antibodies, and,most importantly, interface hepatitis on liver biopsy

Primary biliary cirrhosis (PBC) is a chronic inflammatory

disease of the interlobular and septal intrahepatic bile

ducts Destruction of these small ducts leads to

ductope-nia and retention of bile in hepatocytes Cholestasis causes

hepatocyte damage, which promotes progressive fibrosis

and eventual cirrhosis Ultimately, liver failure and death

ensue unless liver transplantation is available

Diagnosis

Antimitochondrial Antibodies

The identification of antimitochondrial antibodies (AMAs)

as the serologic hallmark of PBC greatly improved the

diag-nostic sensitivity and specificity of this disease These

nonorgan-, nonspecies-specific antibodies are directed at

the 2-oxoacid dehydrogenase enzymes located on the inner

mitochondrial membrane Using sensitive enzyme-linked

immunosorbent assay or immunoblotting, AMAs can be

detected in 95% of patients with histologic and clinical

fea-tures of PBC, and they are rarely associated with any other

clinical condition They may occasionally be found in

oth-erwise clear-cut autoimmune hepatitis but, fortunately, are

not seen with any other chronic cholestatic liver diseases

Along with AMAs, other laboratory features of PBC include

elevation of serum alkaline phosphatase and γ-glutamyl

transpeptidase, a pattern typical of anicteric cholestasis, an

elevated immunoglobulin (Ig)M, and high total cholesterol

Liver Biopsy

Because of the high degree of specificity of AMAs, some

authors have questioned the need for liver biopsy in all

patients with PBC In middle-aged women with fatigue,

pruritus, cholestatic enzyme pattern, high IgM, and

posi-tive AMAs, a liver biopsy is certainly not necessary to make

a diagnosis of PBC However, it does potentially provide

some utility in terms of prognostication The staging

sys-tem initially introduced by Scheuer in 1967 and further

developed by Ludwig and colleagues in 1978 is still in

com-mon use The histologic pattern is graded from I to IV, with

stage I disease showing only portal inflammation with duct

injury (+/−granulomata) and stage IV disease

represent-ing established cirrhosis Although it has been suggested

702 / Advanced Therapy in Gastroenterology and Liver Disease

Although corticosteroid therapy has been advocated for

this group of patients, they appear to respond as well to

ursodeoxycholic acid (UDCA) therapy as patients with

PBC alone

In a small number of patients, the clinical, biochemical,

and histologic features of PBC will be present in the

absence of AMA (even on repeated testing using highly

sensitive methods) These patients tend to have circulating

antinuclear antibody or smooth muscle antibodies, often

in high titer Before making a diagnosis of AMA-negative

PBC, biliary tract imaging with magnetic resonance

cholangiopancreatography or endoscopic retrograde

cholangiopancreatography is imperative to exclude

pri-mary sclerosing cholangitis and/or biliary obstruction

Natural History

As PBC is diagnosed at earlier and earlier stages of the

dis-ease, the natural history is becoming more clearly defined

It seems that there is likely a preclinical stage in which

patients test AMA positive in serum but have normal liver

biochemistry Some of these patients will already have the

histologic features of PBC on liver biopsy, and at 10-year

follow-up, the majority develop cholestasis, many with

symptomatic disease Once biochemical cholestasis occurs,

patients may be symptomatic or asymptomatic, and this

appears to affect prognosis The initial report on

asympto-matic PBC suggested that over 10 years, 50% become

symp-tomatic Data from the controlled treatment trials of PBC

suggest that about one-third of asymptomatic patients will

develop symptoms within 5 years The longest studies of

natural history suggest that asymptomatic PBC tends to

progress considerably more slowly than symptomatic PBC,

with a mean survival of 8 years for symptomatic disease and

16 years for asymptomatic disease Because many patients

do not present until later life and PBC is a slowly

progres-sive disease, it is important to consider that PBC may not

affect a given individual’s life expectancy In fact, in a study

from northern England, 54% of asymptomatic patients

with PBC died of causes other than their liver disease

RISKSCORES

A number of risk scores have been developed to predict

prognosis in PBC None have found the severity of

symp-toms, titer or presence of AMA, or height of serum alkaline

phosphatase or aminotransferases to be of prognostic value

In contrast, serum bilirubin has proven useful in all of the

various risk scores The most widely used risk score comes

from the Mayo Clinic and, conveniently, does not require a

liver biopsy to be performed for calculation It takes into

account age, serum albumin, prothrombin time, and the

presence of fluid retention with or without diuretic use The

Mayo risk score has been shown to be valid in patients on

UDCA therapy and those undergoing liver transplantation

Therapy

Management of PBC can be divided into the following

major components: (1) symptomatic/preventive therapy and (2) disease-modifying therapy (Table 121-1) Although

much attention is focused on disease-modifying therapy,often preventive strategies and alleviation of symptoms aremore important to patients

Symptomatic Therapy

The most prevalent symptoms affecting patients with PBC

are fatigue and pruritus Both can be extremely

debilitat-ing and significantly impact on patients’ quality of life

FATIGUEUnfortunately, to date, no good therapy exists to managefatigue in patients with PBC There are many anecdotal

reports that UDCA improves fatigue, and pilot studies of

methotrexate (MTX) suggested that it may be effective for

this purpose as well Although targeted therapy may notmarkedly affect fatigue in PBC, it is important to ensure

that there are no other contributing factors Hypothyroidism

is commonly associated with PBC and should be excluded.Fatigue is extremely common in the general population and

is often multifactorial It is important to take a good sleep

history and to identify and correct any bad habits that may

be worsening fatigue Some common problems include

TABLE 121-1 Strategies for Prevention and Management of Primary Biliary Cirrhosis Symptoms and Complications

hypothyroidism

Rifampicin 150 mg bid Naltrexone 50 mg od (use cautiously) Ultraviolet light exposure

Regular dental follow-up Pilocarpine

If osteoporosis—bisphosphonates Hormone replacement therapy (use cautiously) Calcitonin

Cholestyramine (first line)

“Statins” safe (if needed)

bid = twice daily; od = once daily.

Primary Biliary Cirrhosis / 703

excessive caffeine and/or nicotine use, obesity with or

with-out sleep apnea, use of sedatives that may impair sleep

qual-ity, and lack of exercise Often improvement of one or more

of these factors may make the difference between

manage-able and unmanagemanage-able fatigue

PRURITUSAlthough the specific cause of pruritus is unknown, there is

a range of therapeutic options for this troublesome

symp-tom Although bile acids per se are not likely the cause of

pruritus, there is clearly a pruritogen in bile Consequently,

the use of cholestyramine as a binding agent is generally very

successful for cholestasis-induced pruritus It is given before

and after breakfast to coincide with maximal gallbladder

emptying Although effective, it is important to warn patients

that it may cause constipation and that it will bind all

med-ications taken within 4 hours of ingestion, including UDCA

If patients take cholestyramine in the morning, it is best that

they take UDCA, calcium, and vitamin D in the evening If

cholestyramine is not well tolerated or is ineffective, the

anti-tuberculous medication rifampicin can be used Although

rifampicin can occasionally cause a hepatitis, this is

gener-ally seen only when used in combination with isoniazid At

the dose of 150 mg twice daily, adverse effects (aside from

orange urine) are not generally seen However, a recent

report of three cases of rifampicin-induced hepatitis in

patients with PBC stresses the importance of clinical

follow-up in all patients on this medication Opiate antagonists can

be used if the above two medications are ineffective It is

believed that endogenous opioids may be overproduced in

the liver in PBC and other chronic cholestatic conditions

Although reportedly effective, these agents should be used

with caution because severe opiate withdrawal-type

reac-tions have been reported Generally, naltrexone is used at a

dose of 50 mg daily Some patients have also reported

improved fatigue with opiate antagonists Antihistamines

should not be used to treat PBC-induced pruritus because

they will not be effective and may contribute to fatigue

Exposure to ultraviolet light in the absence of sunblock is

often helpful for pruitus as well If pruritus is intractable and

unresponsive to all agents, consideration of liver

transplan-tation on this basis alone should be given It is noteworthy

that pruritus often improves as the disease progresses

SJÖGREN’SSYNDROME

A symptom that is often underappreciated by physicians

is sialoadenitis or full-blown Sjögren’s syndrome This is

present in up to 93% of patients with PBC and can be quite

troublesome Patients may not report symptoms of dry

eyes or dry mouth unless directly asked Dry eyes can

usu-ally be managed with artificial teardrops It is important

that patients with complaints of dry mouth regularly see a

periodontist to ensure that they do not develop gingival

disease If drinking water and chewing sugarless gum areinadequate, use of pilocarpine and other standard thera-pies for Sjögren’s syndrome has been reported with goodsuccess All affected individuals should be advised to swal-low pills with plenty of water while standing up Finally,women should be asked directly if they have problems withvaginal dryness because they rarely report this sponta-neously Management with lubricants is usually adequate

In addition to the specific symptoms of PBC, it is alsoworthwhile to consider associated diseases Rheumatoidarthritis; Raynaud’s phenomenon with or without sclero-derma; calcinosis, Raynaud’s phenomenon, esophageal dys-function, sclerodactyly, and telangiectasia (CRESTsyndrome); thyroiditis; and celiac disease are all associatedwith PBC and should be investigated as necessary

Preventive Therapy

Because PBC is a progressive disease that often eventuallyresults in the need for liver transplantation, it is particularlyimportant that patients remain as healthy as possible toimprove their long-term outcome The major preventable

complications of PBC include osteoporosis and variceal

hem-orrhage However, it is important to counsel patients on

other modifiable lifestyle choices as well Particular tion should be paid to smoking and obesity because both

atten-have the potential to modify transplantation outcome

OSTEOPOROSIS

It remains somewhat controversial whether osteoporosis istruly a complication of PBC Although it is common amongpatients with PBC, this disease affects predominantlymiddle-aged women who are at risk for osteoporosis forother reasons In any case, patients should be screened forosteopenia or osteoporosis using bone densitometry All

patients with PBC should take calcium and vitamin D, either

as a supplement or as part of their regular diet The

bis-phosphonate etidronate has been shown to be safe in PBC,

stabilizing bone loss in corticosteroid-treated patients.Caution should be used with these agents if patients havesignificant esophageal varices because of the risk ofesophageal ulceration Newer-generation bisphosphonates

such as risedronate (Actonel) are likely safer, although no

data specifically addressing this question are currently

avail-able Other options include hormone replacement therapy,

which has been shown not to worsen cholestasis in PBC butmust be used with caution given the recent Women’s Health

Initiative trial, and calcitonin UDCA therapy has not been

shown to improve osteoporosis in PBC

ESOPHAGEALVARICESUnlike with most forms of chronic liver disease, the pres-ence of esophageal varices in PBC does not necessarily indi-cate the presence of cirrhosis The granulomatous

704 / Advanced Therapy in Gastroenterology and Liver Disease

destruction of the bile ducts can also obliterate small portal

vein branches, resulting in presinusoidal noncirrhotic portal

hypertension, similar to that seen in hepatic sarcoidosis As

a consequence, patients with PBC may have significant

por-tal hypertension even with fairly early, noncirrhotic-stage

PBC; therefore, upper endoscopy to screen for varices should

be performed at diagnosis If present, varices should be

man-aged with β-blockade and band ligation as appropriate No

validated interval for variceal screening has been identified

We have shown that it is very unlikely for patients to have

varices with a platelet count of≥200,000/µL as a surrogate

marker for hypersplenism secondary to portal hypertension

Consequently, endoscopy is performed every 1 to 2 years in

those with platelets <200,000/µL Because variceal

hemor-rhage may not be a consequence of end-stage liver disease

in PBC, a single bleed is generally not considered an

indica-tion for liver transplantaindica-tion

HEPATOCELLULARCARCINOMA

Although not preventable, hepatocellular carcinoma

(HCC) is another important complication of PBC that

requires mention Although the prevalence of HCC in

patients with PBC ranges widely in different studies, recent

data suggest that the incidence of HCC among cirrhotic

patients with PBC is similar to that found in patients with

hepatitis C–induced cirrhosis Consequently, as for patients

with cirrhosis from chronic hepatitis C virus infection,

patients with PBC should have screening sonograms once

they have radiographic or histologic evidence of cirrhosis

HYPERCHOLESTEROLEMIAOne final point regarding preventive therapy is the issue of

hypercholesterolemia Increased total cholesterol is

com-mon in PBC and is believed to result from chronic

cholestasis This has naturally raised concerns about

car-diovascular effects A recent study confirmed earlier

find-ings that there was no increased cardiac death among

patients with PBC In general, cholesterol levels will fall

with cholestyramine therapy for pruritus and tend to come

down as the disease progresses If patients have other

car-diac risk factors, there is no concern with using

3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase

inhibitors (statins), although they may not be necessary

Disease-Modifying Therapy

Many randomized controlled trials (RCTs) of a number of

different agents have been performed in patients with PBC

Because PBC is such a slowly progressive disease, it takes

many years with large numbers of patients to perform an

adequately powered trial of a new therapy Unfortunately,

most of the studies in PBC have been significantly

under-powered and of short duration and have lacked valid end

points, making the results very difficult to interpret As a

compromise, meta-analyses have been performed bining the raw data from numerous small trials Althoughgenerally a reasonable strategy, it is important to ensurethat all trials included are of similar quality; this has notalways been the case

com-A variety of different types of agents have been used totreat PBC Because it is thought to be an autoimmune dis-

ease, many different immunosuppressive agents have been tried In addition, antifibrotic and anticholestatic agents have

been studied to see if they may slow down disease gression Because of the likely need for very prolonged ther-apy to combat this slowly progressive disease, long-termcomplications of therapy are critical to consider It isimperative to ensure that such complications are not worsethan the disease itself

pro-Immunosuppressive agents that have been studied in PBC

include azathioprine, cyclosporine, MTX, prednisolone,

chlo-rambucil, thalidomide, and budesonide (Table 121-2) None

of these agents have been shown to be useful in a

prop-erly conducted RCT MTX has probably received the most

attention because of early promising pilot studies In theonly RCT, no benefit was seen, and, in fact, the patients tak-ing MTX had higher serum bilirubin values and Mayo riskscores with a trend to worsened survival at the end of 5years, suggesting that MTX may, in fact, be toxic in PBC

D -Penicillamine and colchicine have been studied to see

if they may reduce fibrogenesis in PBC There have beeneight RCTs ofD -penicillamine, but the results have been

uniformly disappointing, with significant adverse effects

and no survival benefit Colchicine has been studied in three

small RCTs Although two of the three studies showed animprovement in liver synthetic function (ie, albumin andbilirubin), the benefit on histology or survival is doubtful

URSODEOXYCHOLICACID

UDCA is a hydrophilic bile acid that appears to have its effect

by reducing exposure of hepatocyte membranes to the toxiceffects of retained endogenous hydrophobic bile acids It alsoreduces bile acid absorption in the terminal ileum and up-regulates the canalicular transporter Mrp2, which mayexplain its pronounced effect on serum bilirubin levels.UDCA was first studied in the early 1980s, and now a total

of 16 RCTs have been performed and analyzed in multiplemeta-analyses The most recent meta-analysis comes fromthe Cochrane Library in which Gluud and Christensen com-bined the data from all of these rather heterogeneous stud-ies; treatment periods ranged from 6 months to 4 years, with

a daily dose of UDCA from 7.7 to 15 mg/kg, and there was

a range of disease severity In addition, the majority of thetrials (11 of 16) were of poor methodologic quality.Attempting to take all of this into consideration, the authors

concluded that there was no survival benefit at 2 years, but

patients who received UDCA for 4 years or longer had a nificant delay to time for liver transplantation Examining liver

sig-Longo M, Crosignani A, Battezzati PM, et al Hyperlipidaemic

state and cardiovascular risk in primary biliary cirrhosis Gut

2002;51:265–9.

Metcalf JV, Mitchison HC, Palmer JM, et al Natural history of

early primary biliary cirrhosis Lancet 1996;348:1399–402.

Prince M, Chetwynd A, Newman W, et al Survival and symptom

progression in a geographically based cohort of patients with

primary biliary cirrhosis: follow-up for up to 28 years.

Gastroenterology 2002;123:1044–51.

Prince MI, Burt AD, Jones DE Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis Gut 2002;50:436–9.

Tinmouth J, Tomlinson G, Heathcote EJ, Lilly L Benefit of transplantation in primar y biliar y cirrhosis between 1985–1997 Transplantation 2002;73:224–7.

Wolfhagen HF, Sternieri E, Hop WC, et al Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo- controlled study Gastroenterology 1997;113:1264–9.

706 / Advanced Therapy in Gastroenterology and Liver Disease

logic means (eg, central administration of morphine) is

associated with pruritus, which can be effectively treated

with opiate antagonists Opiate antagonists have been

shown to decrease the pruritus of cholestasis and thebehavioral manifestation of pruritus, scratching, in con-trolled clinical trials that applied objective methodology.These results support the idea that the pruritus ofcholestasis results from increased opioidergic tone, atleast in part A central mechanism for the pruritus ishypothesized The nature of the pruritogenic com-pound(s) with affinity for opioid receptors, however, isnot known

In examining patients with pruritus associated withcholestasis it is necessary to rule out contributing causes

to the pruritus, including dermatological conditions,which, in contrast to the pruritus of cholestasis, manifestwith pruritic skin lesions, in general Pruritus can resultfrom nondermatologic conditions different from cholesta-sis including medications, altered thyroid function, andmalignancy It is prudent, therefore, to rule out possiblecontributing factors to the pruritus, even in patients withcholestasis, by performing a well-planned investigation (eg,thyroid function tests, dermatologic examination)

Therapy for the Pruritis of Cholestasis

A list of some of the therapies for the pruritus of sis is provided in Table 122-1

cholesta-Interventions Aimed at the Removal of the

Cholestyramine is the most widely used medication

pre-scribed to treat the pruritus of cholestasis Many patients

respond to cholestyramine with a decrease in their

pruri-Cholestasis is defined as impaired secretion of bile It is a

complication of liver disease characterized by the

accu-mulation in plasma of substances that are excreted in bile

under physiological conditions, including bile acids,

cho-lesterol, and bilirubin In this chapter the sequelae of

cholestasis with emphasis on management will be

dis-cussed

The Pruritis of Cholestasis

Pruritus is one of the most common complications of

cholestasis, but its etiology is unknown It is a

well-recognized manifestation of primary biliary cirrhosis

(PBC) and primary sclerosing cholangitis (PSC), but

con-ditions not usually associated with a serum liver profile

classic for cholestasis (eg, predominantly increased

activ-ity of alkaline phosphatase and γ-glutamyl transpeptidase),

including liver disease secondary to chronic hepatitis C

(HC), can also be associated with pruritus The pruritus of

cholestasis can be severe; it is an indication for liver

trans-plantation in cases of intractability

It is inferred that the pruritus of cholestasis results from

the accumulation of pruritogens that are excreted in bile

under normal conditions and that accumulate in tissues,

including plasma, as a result of cholestasis In support of a

hepatic origin of the pruritogen(s) is the disappearance

of the pruritus after liver transplantation; in support of the

biliary excretion of pruritogen(s) is the relief of the

symp-tom after resolution of biliary tract obstruction

Bile acids, which accumulate in tissues as a result of

cholestasis, have been implicated in the pathogenesis of the

pruritus Thus far, there are no scientific data that

con-vincingly support a role of bile acids in this type of

pruri-tus Histamine, which was reported to accumulate in

plasma in patients with cholestasis, has also been

impli-cated in the pathogenesis of the pruritus The

character-istics of histamine-mediated pruritus (ie, cutaneous edema

and erythema), however, are absent from the skin of

patients with the pruritus of cholestasis, although skin

lesions secondary to chronic scratching are common

The opiate withdrawal-like reaction that patients with

cholestasis can experience after the administration of

opiate antagonists suggests that in cholestasis central

neu-Chronic Cholestasis and Its Sequelae / 709

amelioration of the pruritus of cholestasis Prescribing

anti-histamines in a patient in whom there is no relief

associ-ated with that class of drugs serves little purpose unless the

sedative effect of antihistamines helps patients to sleep A

limiting factor to the use of antihistamines is the dryness

of mucous membranes with which they are associated and

which in patients with PBC and Sjögrens’s syndrome is

problematic

Hepatic Enzyme Inducers

Hepatic enzyme inducers including phenobarbital and

rifampicin are used to manage patients with the pruritus

of cholestasis The reported ameliorating effect of the

pru-ritus of cholestasis by phenobarbital is not sustained for a

prolonged period of time The risk and benefits of

seda-tion have to be taken into account when prescribing this

drug Rifampicin has been used to treat the pruritus since

the late 1980s At doses between 300 to 450 mg/d or

10 mg/kg, rifampicin has been reported to improve the

pru-ritus of cholestasis secondary to PBC as assessed

subjec-tively In one of the controlled studies, this drug appeared

to be more effective than phenobarbital in inducing

ame-liorations of pruritus The mechanism of the reported

antipruritic effect of rifampicin is unknown There are

reservations to the use of rifampicin to treat patients with

cholestasis and pruritus because of its potential for liver

toxicity Follow-up of liver tests is necessary if this drug is

to be prescribed

Opiate Antagonists

Opiate antagonists to treat patients with the pruritus of

cholestasis have been studied in controlled studies in which

quantitative methodology was applied to generate an

objective efficacy endpoint (change in scratching activity)

Continuous infusions of the opiate antagonists naloxone

(0.2 µg/kg/hr) preceded by 0.4 mg administered as an

intravenous (IV) bolus and the oral administration of the

drug nalmefene were associated with significant reductions

in scratching activity, the behavioral manifestation of

pru-ritus, and in its perception These results support the

hypothesis that the pruritus of cholestasis is mediated, at

least in part, by a mechanism that involves the endogenous

opioid system and provide a rationale for the use of opiate

antagonists in the treatment of this form of pruritus Thus,

the treatment is specific Naltrexone, an orally bioavailable

opiate antagonist, has also been studied in clinical trials

that applied subjective methodology including two placebo

controlled studies Doses of 25 mg twice a day increased to

a single 50 mg dose per day were associated with decreased

pruritus at short term

A concern regarding the use of opiate antagonists in

patients with cholestasis and pruritus is the opiate

withdrawal-like reaction that this class of drugs may

pre-cipitate in these patients The only opiate antagonist

avail-able in the United States for oral administration is

nal-trexone, in 50 mg capsules, which could be high at initiation

of treatment in some patients To prevent or minimize thepotential opiate withdrawal-like reaction, patients can beadmitted to the hospital for initiation of treatment with

ultra low doses of IV naloxone (0.002 µg /kg/min) by tinuous infusion, gradually increasing the dosage of 0.2

con-to 0.8 µg/kg/min for 48 hours, for example, depending on

the patients’ response, and to start oral naltrexone at the

lowest possible dose This option requires that the tablet

be divided, ideally, in the hospital pharmacy (eg, 4 pieces,12.5 mg/quarter pill) The final oral dose depends on the

response of the patient As oral naltrexone is introduced, the naloxone infusion is gradually decreased and discon- tinued A recent publication on naltrexone in patients with

alcoholism did not report hepatotoxicity; however, the

potential hepatotoxicity of naltrexone exists, especially in

patients with liver disease Pharmacokinetic studiesrevealed that in decompensated liver disease, there is accu-

mulation of naltrexone metabolites, but it is unusual for

patients whose hepatic function has deteriorated to rience pruritus because pruritus tends to cease as syntheticfunction decreases Nevertheless, monitoring of serumactivity of liver-associated enzymes is recommended when

expe-patients with liver disease are treated with naltrexone.

Patients who are very distressed by their pruritus rant admission to the hospital for management and forpsychiatric examination for general support or treatment

war-if suicidal actions are a concern In these patients naloxoneinfusions can be tried as described above

Serotonin Antagonists

Pruritus is a nociceptive stimulus The serotonin system isinvolved in the mediation of nociception Like the opioidsystem, the serotonin system may also mediate pruritus.There are no data in support of altered neurotransmissionvia the serotonin system in cholestasis, but increased centralopioidergic tone can result in increased serotoninergic tone

Ondansetron is an antagonist at the type-3 serotonin

recep-tor (5-HT3), which is found both in the central nervous tem and in peripheral nerves IV bolus administrations of

sys-ondansetron (4 or 8 mg) were reported to be associated with

a decrease in pruritus lasting for several hours in a placebocontrolled study In a short term placebo controlled study

that included 18 patients, oral ondansetron was associated

with a small, but significant decrease in pruritus, as sured by a visual analogue scale In contrast to these stud-ies that applied subjective methodology, in a study in which

mea-scratching activity was measured, IV ondansetron followed

by its oral preparation was not associated with a decrease

in scratching activity or in the perception of pruritus overplacebo The different results obtained in these studies may

be attributable to the differences in their design, but they

710 / Advanced Therapy in Gastroenterology and Liver Disease

also emphasize the importance of behavioral methodology

in studies of pruritus

Along the lines of serotonin neurotransmission, a

ret-rospective review published in abstract form stated that

patients with PBC had reported improvements in their

pruritus associated with sertraline, a selective serotonin

reuptake inhibitor (SSRI) How a SSRI (ie, sertraline) as

well as an antagonist at the serotonin type-3 receptor (ie,

ondansetron) may relief the pruritus of cholestasis is not

known If these reports are confirmed in properly

con-trolled clinical trials, studies of the serotonin system in

cholestasis may be warranted

Three patients with cholestasis were reported to

expe-rience relief of their pruritus after the administration of

dronabinol, an agonist at the cannabinoid receptor.

Experimental data suggest that the endocannabinoid

sys-tem participates in the mediation of nociception, but how

this relates, if at all, to pruritus is unknown

Modalities That Escape Classification As Antipruritic

Interventions

Propofol is an anesthetic with some anti-opiate activity At

subhypnotic doses, propofol was reported to ameliorate the

pruritus of cholestasis in an open label study and in a

double-blind cross-over placebo-controlled trial that

included 10 patients S-adenosylmethionine (SAMe) was

reported to ameliorate the pruritus of cholestasis in a group

of patients It has antidepressant properties If the

antipru-ritic effect of SAMe is real, a central mood-enhancing effect

of the drug, which may have an impact on how pruritus is

experienced or may change the central component of

pru-ritus, may play a role in the reported antipruritic actions

Phototherapy to the skin with ultraviolet (UV) light B is

used by some clinicians UV B treatment in erythemogenic

doses is one of the treatments of psoriasis There is no

apparent rationale to use this intervention in the treatment

of the pruritus of cholestasis The effect of UV B treatment

on this type of pruritus is highly questionable

It is not possible to make general recommendations

regard-ing the use of the treatments described in this last section

because of the limited available data

Other therapeutic modalities that have been used to

treat the pruritus of cholestasis include flumecinol,

ligno-caine, antioxidants, and androgens, and are stated here for

completion Ursodeoxycholic acid (UDCA) is a drug

approved to treat PBC UDCA treatment may be

associ-ated with some improvement in pruritus by virtue of the

impact it has on the liver disease per se The effect of UDCA

as a specific antipruritogen has not been studied and based

on clinical trials of UDCA in PBC, it is uncertain; however,

the choleretic effect of UDCA may have a beneficial impact

on the pruritus by the presumed enhanced biliary

excre-tion of pruritogen(s) Exacerbaexcre-tion of pruritus upon

start-ing a regimen with UDCA is reported by some patients

(NV Bergasa, unpublished observations)

The Fatigue of Cholestasis

Patients with cholestasis can experience fatigue, which can

be profound It is one of the most common symptomsassociated with PBC Patients with HC commonly reportfatigue It is uncertain whether the fatigue experienced bypatients with HC is specific for that condition and differ-ent from the fatigue of liver disease in general

The etiology of the fatigue of cholestasis is unknown.Central and peripheral components for the fatigue ofcholestasis have been suggested In one of the first studiesthat addressed fatigue in PBC, the presence of this symp-tom, as measured by questionnaires, was associated withpoor sleep quality and with depression; this finding sug-gested that fatigue may be, in part, centrally mediated as

it had been editorialized previously

Increasing serotoninergic tone by the administration of

paroxetine was associated with worse performance in male

athletes on a bicycle ergometer These results could not beexplained by variations in exercise intensity or by metabolic

or respiratory factors Supporting the idea that enhancedserotonin neurotransmission may be associated with fatigue

is a case report of a patient with HC and fatigue whoreported increased energy level (ie, “decreased fatigue”)

associated with the administration of ondansetron, a

sero-tonin antagonist at the type-3 receptor Increased dergic tone in cholestasis (for review) may also contribute

opioi-to the fatigue In a study of patients with cholestasis, most

of who had PBC, a decrease in fatigue, as assessed by a visualanalogue scale, was reported after the administration of the

opiate antagonist nalmefene Recently, a beneficial effect of

naloxone infusions (0.2 µg/kg/min) on the degree of fatigue,

assessed by a visual analogue scale, was reported A severeopiate withdrawal-like reaction was also reported in thispatient This side effect supports the idea of increased opi-oidergic tone in cholestasis

Serotonin Antagonists

There is no specific treatment for the fatigue of sis at present The methodology to study fatigue is sub-jective; thus, there is substantial uncertainty in interpretingany data on fatigue Some patients with PBC report thattaking naps during the day facilitates the performance oftheir daily activities (NV Bergasa, unpublished) The exam-ination of patients with fatigue and liver disease includesthe exclusion of conditions that have a negative impact onenergy level, including anemia, thyroid dysfunction,adrenal and renal insufficiencies, and depression, in orderfor specific treatments to be prescribed if those conditionsare present

cholesta-Chronic Cholestasis and Its Sequelae / 711

The use of ondansetron at doses of 4 mg orally 3 times

a day in patients with PBC was associated with a decrease

in fatigue scores as assessed by the Fisk Fatigue Impact

Score (FFIS), as published in abstract form Headache and

constipation were the most common side effects associated

with ondansetron These preliminary results may support

the idea that altered serotoninergic neurotransmission

con-tributes to the pathogenesis of fatigue in liver disease Table

122-2 summarizes the experience with ondansetron in the

treatment of fatigue to date

Aerobic Exercise

Aerobic training increases maximal work capacity, which

leads to a reduction in the percentage of total capacity

required for activities of daily living This reduction is

asso-ciated with decreased fatigue Aerobic training achieved

during an 8-week structured exercise program was

associ-ated with a decrease in fatigue as assessed with

question-naires in 3 patients with chronic HC These preliminary

results support the conduct of studies of aerobic training

for the treatment of fatigue secondary to liver disease

Hypercholesterolemia

Hypercholesterolemia is a complication of cholestasis

Hypercholesterolemia has been classically reported in

patients with PBC Xanthomas and xanthelasmas can be

identified in the skin of patients with PBC and

hypercho-lesterolemia Data available tend to suggest that high

den-sity lipoprotein is the dominant lipid fraction present in

the serum of patients with PBC and hypercholesterolemia

Higher concentration of Apo(a) in the plasma of patients

with PBC than in that of the control groups that have been

included in the studies has been interpreted as being

pro-tective against complications secondary to atherosclerosis

The limited epidemiologic data available from

retrospec-tive studies indeed do not suggest that patients with PBC

have a high risk for complications due to atherosclerosis

This observation, in conjunction with the characteristic

lipid profile of PBC, has not supported the specific

treat-ment of hypercholesterolemia in these patients One study

reported that patients with PBC and marked terolemia were not at an increased risk for cardiovascularcomplications, whereas patients with moderate hypercho-lesterolemia were; this finding suggested the existence ofprotective factors in the former group It may be thatpatients with PBC and hypercholesterolemia who have riskfactors for adverse cardiovascular events in addition to highcholesterol benefit from treatment with lipid loweringdrugs Indeed, myocardial infarction was reported inpatients with PBC in one published series At present, thereare no recommendations on the treatment of hypercho-lesterolemia in patients with PBC but it seems prudent torefer patients with hypercholesterolemia at risk for car-diovascular events, as determined by calculated lipid ratios,

hypercholes-to lipid experts for an evaluation and recommendation.PSC can also be associated with hypercholesterolemia.There is less information in PSC than in PBC from which

to build recommendations regarding treatment; thus, ral to lipid experts is the best approach It is emphasizedthat in contrast to PBC, there are no data suggesting a lowrisk for adverse cardiovascular events in patients with PSC

refer-Malabsorption

Cholestasis results in decreased concentrations of bile acids

in the intestine Malabsorption of fat and fat-soluble mins ensue when the concentration of bile acids fall below

vita-a criticvita-al micellvita-ar concentrvita-ation Deficiency of fvita-at-solublevitamins, A, D, E, and K, tend to correlate with durationand degree of cholestasis Some degree of maldigestion mayalso exist in liver disease

Fat Malabsorption

Fat malabsorption can accompany chronic liver disease butthe degree of steatorrhea is modest, with over 70% of theingested fat being absorbed In patients with PBC, an asso-ciation with celiac disease has been reported Thus, inpatients with PBC and suggestion of malabsorption of fat

or other specific deficiencies (eg, magnesium, iron) celiacdisease should be excluded because the treatment for thiscondition is specific (ie, gluten-free diet) Screening for

TABLE 122-2 Selected Reports on the Treatment of Fatigue of Liver Disease

Dose/Mode of

bid = twice daily; FFIS = Fisk Fatigue Impact Score; NA = not applicable; PO = by mouth; tid = 3 times daily

*Patients had fatigue associated with liver disease secondary to chronic hepatitis C infection.

† Fatigue assessed with a questionnaire from which the FFIS is derived.

712 / Advanced Therapy in Gastroenterology and Liver Disease

celiac disease in patients with PBC and vice versa is a topic

of current discussion that will not be addressed in this

chapter

Important fat malabsorption in patients with cholestasis

can be treated with the administration of medium chain

triglycerides It is noted that pancreatic insufficiency can be

associated with PBC, considered to result from decreased

pancreatic secretion, resulting from the “dry gland syndrome”

as PBC has been suggested to be Pancreatic insufficiency

requires specific treatment with supplemental pancreatic

enzymes as described in another section of this book

Vitamin Deficiencies

Vitamin A is available from animal dietary sources as

retinol and from plant sources as β-Carotene The uptake

of retinol by intestinal cells is regulated by retinol binding

protein.β-Carotene depends on bile acid availability in the

small intestine for absorption In addition to poor

absorp-tion secondary to bile acid deficiency, decreased

availabil-ity of retinol binding protein, which results from chronic

hepatobiliary disease, contributes to vitamin A deficiency

because of impaired released of the vitamin from liver

stores Enhanced urinary clearance of retinol due to

defi-ciency in transhyretin, a thyroxine binding globulin to

which retinol binding globulin is bound in the circulation,

may also occur Deficiency in vitamin A usually manifests

itself as impaired dark adaptation, of which patients may

not be aware; accordingly, opthalmological referral is

nec-essary for a complete examination in patients at risk for

deficiency The activation of retinol to a photochemical

compound and the hepatic secretion of retinol binding

protein depends on zinc; thus, it is necessary to check zinc

levels and correct a deficiency if present Oral doses of

25,000 IU/d to 30, 000 IU 3 times a week have been

rec-ommended for vitamin A supplementation Vitamin A can

be toxic to the liver and to other organs; accordingly, it has

to be administered under supervision not to exceed what

are considered normal levels

The most important source of vitamin D in human

beings is endogenous production The metabolism of

vit-amin D has been reported to be normal at least in patients

with PBC These facts have suggested that in cholestasis

poor exposure to sunlight by debilitated chronically ill

patient is the main cause of vitamin D deficiency, in

addi-tion to its decreased absorpaddi-tion and renal losses of its

metabolites, which can be enhanced, at least, in PBC

Vitamin D, parathyroid hormone and calcitonin regulate

plasma calcium and phosphorus homeostasis, thus, these

compounds may be abnormal in cases of vitamin D

defi-ciency Doses that have been recommended for vitamin D

supplementation include 400 to 4,000 IU orally per day or

50, 000 IU orally 3 times a week Prolonged

supplementa-tion of vitamin D can lead to hypocalcemia and soft tissue

calcifications

Naturally occurring tocopherols, which require lar solubilization for absorption, is the most abundant

micel-source of vitamin E activity Vitamin E inhibits the

oxida-tion of unsaturated fatty acids, prevents lipid peroxidaoxida-tionand it is a scavenger of free radicals Vitamin E deficiencymanifests itself with a neurological syndrome character-ized by peripheral neuropathy, cerebellar degeneration, andabnormal eye movements Retinal degeneration has beenascribed to vitamins E and A deficiencies alone or com-bined In children the complications of vitamin E defi-ciency are more severe than in adults with cholestasis.Recommendations to treat deficiency of vitamin E include

2 to 20 IU ofα-tocopherol by mouth daily, 100 mg twice

a day or 10 to 25 IU/kg/d

Two forms of vitamin K contribute to vitamin K

activ-ity; K1, or phytonadione, is found in most vegetables and

K2, a series of menaquinones, is formed by gram-positivebacteria in the intestine Other compounds that have vit-

amin K activity are structurally related to menadione.

Vitamins K1and K2 require micellar solubilization forabsorption in the small intestine Vitamin K deficiency maypresent with coagulopathy, as measured by prolonged PTsecondary to deficiency of vitamin K dependent clottingfactors, or it may subclinical Coagulopathy from vitamin

K deficiency secondary to cholestasis resolves upon istration of the vitamin, which can be administered sub-cutaneously Vitamin K deficiency can be corrected withdoses of 1 to 10 mg of vitamin K1by the subcutaneousroute daily for 3 consecutive days In patients with chroniccholestasis, vitamin K deficiency may be prevented bymonthly administration of 10 mg of vitamin K The intra-muscular administration of vitamin K, or of any medica-tion, should be avoided in patients with coagulopathybecause of the risk of intramuscular hemorrhage If thecoagulopathy results from hepatocellular failure, it will notresolve with treatment with vitamin K

admin-Prolonged treatment with cholestyramine for pruritus

in patients with cholestasis can worsen vitamin cies and can even contribute to bleeding complications sec-ondary to coagulopathy due to deficiency of vitamin Kdependent clotting factors Vitamin supplementation isnecessary is cases of deficiencies as documented by bloodlevels Periodic check up of serum vitamin levels to pro-vide sufficient but not excessive amounts can guide theprocess of vitamin supplementation, in general Some ofthe recommended regimens to supplement vitamins whendeficient are listed in Table 122-3

deficien-Cutaneous Sequelae of Cholestasis

Hyperpigmentation

The skin of patients with cholestasis may darken.Hyperpigmentation is a classic finding in patients withPBC The pigment is melanin The etiology of the hyper-

Sokol RJ Fat-soluble vitamins and their importance in patients

with cholestatic liver diseases Gastroenterol Clin North Am

1994;23:673–705.

Theal J, Toosi MN, Girlan LM, et al Ondansetron ameliorated fatigue

in patients with primary biliary cirrhosis (PBC) Hepatology

2002;36(Part 2):296A.

Turner IB, Rawlins MD, Wood P, James OF Flumecinol for the

treatment of pruritus associated with primary biliary cirrhosis.

Aliment Pharmacol Ther 1994;8:337–42.

Walt R, Daneshmend T, Fellows I Effect of stanozolol on itching

in primary biliary cirrhosis BMJ 1988;296:607.

Walt RP, Kemp CM, Lyness L, et al Vitamin A treatment for night blindness in primary biliary cirrhosis Br Med J (Clin Res Ed) 1984;288:1030–1.

714 / Advanced Therapy in Gastroenterology and Liver Disease

Chronic cholestasis of at least 6 months duration is thebiochemical hallmark of PSC Alkaline phosphatase is themost commonly elevated liver enzyme, usually to a higherlevel than aminotransferases, which are seldom more than

5 times normal In children, however, aminotransferaselevels may be markedly elevated Serum bilirubin levels usu-ally are normal, but they may be slightly elevated, and inpatients with advanced PSC, they can reach very high levels.Hypergammaglobulinemia occurs in approximately 25% ofpatients, immunoglobulin M levels being the most com-monly elevated component About 80% of patients test pos-itive for perinuclear antineutrophil cytoplasmic antibodies,but these antibodies can also be found in patients with PBCand autoimmune hepatitis, rendering this test nonspecific.Typical cholangiographic findings of PSC include mul-tifocal structuring and beading, usually involving the intra-hepatic and extrahepatic biliary systems Often thestrictures are diffusely distributed and are short and annu-lar Cystic duct and gallbladder are affected in 15% ofpatients The presence of gallbladder polypoid massesshould raise the suspicion of gallbladder cancer

Liver biopsy findings usually are not enough to lish a diagnosis of PSC The classic onion-skin fibrosis may

estab-Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic

cholesta-tic disorder of unknown causation that is frequently

asso-ciated with inflammatory bowel disease (IBD) PSC is

characterized by diffuse inflammation and fibrosis of the

biliary tree and usually leads to biliary cirrhosis, which can

be complicated by portal hypertension and liver failure

Before the widespread availability of endoscopic

retro-grade cholangiopancreatography (ERCP) in the late 1970s,

PSC was considered a rare disease It is now seen as an

important cause of chronic cholestasis in adults and is

increasingly diagnosed in the pediatric population It is

unclear whether the prevalence of the disease has increased,

but emerging data suggest that it has The recognized

asso-ciation of PSC and IBD and the common screening of IBD

patients with liver enzymes have also probably increased

the frequency with which the diagnosis of PSC is made

This greater recognition of the disease and increased

expe-rience have led to greater understanding of the course of

the disease, although the cause and identification of

spe-cific beneficial therapies have eluded investigators so far

The etiology of PSC has remained poorly understood

since the earliest description of the disease The current

thinking is that PSC occurs as a consequence of a

geneti-cally determined dysregulated immune system, resulting

in an uncontrolled inflammatory response in the bile ducts

with destruction and fibrosis and, ultimately, biliary

cir-rhosis The allo- and/or autoantigen(s) that trigger this

restricted inflammatory response in the bile ducts are

unknown Putative agents include bacterial antigens

absorbed through a diseased bowel mucosa, particularly in

patients with underlying IBD, as well as cytotoxic bile acids,

viral infections, and ischemic injury

Clinical Manifestations, Imaging, and Histologic

Features

PSC can affect any age group, and it has been described in

most racial groups It usually occurs among men twice as

commonly as it does among women The average age at

diagnosis is the early forties, but the disease has been

described in children as young as 1 year and adults as old

716 / Advanced Therapy in Gastroenterology and Liver Disease

be seen in less than 15% of biopsy specimens but, when

seen, is highly suspicious of PSC The most commonly used

histologic grading system, proposed by Ludwig and

col-leagues (1986), has the four following stages: stage 1,

por-tal; stage 2, periporpor-tal; stage 3, seppor-tal; and stage 4, cirrhosis

Unfortunately, the histologic changes in patients with PSC

seem to be quite varied from segment to segment of the

same liver at any given point in time

Course of Disease and Prognostic Survival Models

PSC is usually a progressive disease An earlier study

reported a median survival rate from the time of

diagno-sis of 12 years, which was significantly shorter than the

expected survival for the age- and gender-matched general

population Patients with PSC who presented with

symp-toms, however, had a median shorter survival rate of about

8 years, whereas in asymptomatic patients, a median

sur-vival rate of up to 17 years has been reported in more recent

studies, but survival of these asymptomatic patients is still

less than expected for the general age- and gender-matched

population

Diagnosis

DIAGNOSTICCRITERIA ANDDIFFERENTIALDIAGNOSIS

Visualization of the biliary tree is essential for establishing

the diagnosis of PSC ERCP is the diagnostic test of choice,

although magnetic resonance cholangiography (MRC) is

reasonably sensitive and specific for the detection of PSC

and may be a more cost-effective alternative for

establish-ing the diagnosis in patients with suspected PSC

Percutaneous approaches also can be used, but because of

the frequently sclerotic intrahepatic bile ducts, gaining

access to the intrahepatic biliary system by the percutaneous

route can be challenging The availability of MRC as a

screening test for patients with suspected PSC made

non-invasive diagnosis possible The diagnosis criteria for PSC

include typical cholangiographic abnormalities involving

any part of the biliary tree, compatible clinical and

bio-chemical findings (typically prolonged cholestasis), and

exclusion of other causes of secondary sclerosing

cholan-gitis, such as previous biliary tract surgery, bile duct neoplasm,

acquired immunodeficiency syndrome cholangiopathy,

chole-docholithiasis, congenital abnormalities, history of caustic

sclerosis of the bile ducts, ischemic strictures after

trans-plantation, or caustic or chemical injury to the bile ducts

caused by infusion Liver biopsy has been used in the past

to help confirm the diagnosis, although the diagnostic

speci-ficity and sensitivity of the biopsy have come under

ques-tion, particularly in those patients with typical

cholangiographic features of PSC A liver biopsy with

fea-tures compatible with PSC in patients with IBD and chronic

cholestasis, but a normal cholangiogram, is called

small-duct PSC and represents about 5 to 10% of histologically

confirmed cases of PSC Small-duct PSC can progress toclassic PSC with typical cholangiographic features in somepatients whose cases are followed for several years.Given the uncertainty of natural history studies, prog-nostic models based on actual data obtained from patients

at a given point in time have been developed to help moreaccurately predict an individual patient’s prognosis A vari-ety of models have been created; among them, the Mayorisk score is the most widely used The Mayo PSC risk score

is calculated by the following formula:

R = 0.03 (age in years) + 0.54 ×log (bilirubin inmg/dL) + 0.54 ×log (aspartate aminotransferase [AST]

in U/L) + 1.24 (history of variceal bleeding) −0.84 ×

(albumin in g/dL)

Thus, a 50-year-old man with a serum bilirubin of

5 mg/dL, an AST of 140 U/L, one prior gastrointestinalbleed, and an albumin of 2.8 g/dL would have a Mayo PSCrisk score of 1.92 If this patient had another episode ofvariceal bleeding, his Mayo risk score would increase sig-nificantly, even if all other parameters remainedunchanged

Treatment

MANAGEMENT OFCOMPLICATIONS OFPSC

Pruritis Although not common, pruritus can be disabling

and associated with a diminished quality of life, but its ity does not parallel the severity of the liver disease

sever-Cholestyramine (4 g 3 to 4 times daily), several antihistamines,

and rifampicin (150 to 900 mg by mouth daily), as well as oid receptor antagonists (naltrexone 50 mg by mouth daily),

opi-have been used with varying results to treat patients with

cholestatic pruritus First-line therapy is usually

cholestyra-mine; however, rifampicin is effective and is frequently needed

for patients not responding to the bile acid binding resins.There is a separate chapter on chronic cholestasis (see Chapter

122, “Chronic Cholestasis and Its Sequelae”)

Vitamin Deficiency As many as 40% of patients are

defi-cient in vitamin A, whereas 14% are defidefi-cient in vitamin Dand 2% are deficient in vitamin E These vitamin-deficientpatients should receive vitamin replacement therapy (vita-min A, 100,000 IU PO per day for 3 days, then 50,000 IU/day

PO for 14 days; vitamin D, 25,000 to 50,000 U 2 to 3 times

a week; vitamin E, 400 U daily) Vitamin K deficiency isuncommon, but if suspected, a short trial of water-soluble

vitamin K (Mephyton [phytonadione], 5 mg/dL) can be

con-sidered If the prothrombin time responds after a few doses,long-term therapy should be recommended

Osteoporosis Metabolic bone disease, usually caused by

osteoporosis instead of osteomalacia, is relatively common

in patients with PSC Glucocorticoids used to treat

accom-Primary Sclerosing Cholangitis and Cholangiocarcinoma / 717

panying IBD aggravate the osteoporosis There is no proven

treatment that will help these patients, but they may

ben-efit from oral administration of vitamin D and calcium,

particularly those with bone density in the range of

osteopenia (T score < −1) or established osteoporosis (T

score below −2.5) Bisphosphonates have been used with

varying results to treat patients with PBC but have not been

tested in the care of patients with PSC Steatorrhea can

occur in patients with PSC owing to diminished bile acids

delivered to the intestine, or it may be due to chronic

pan-creatitis, or celiac disease, which can co-exist with PSC All

of these conditions should be considered in the evaluation

of steatorrhea in the setting of PSC

Biliary Strictures Dominant biliary strictures occur in

about 10% of patients with PSC, usually in the

extrahep-atic biliary system, and are associated with jaundice,

pru-ritus, or recurrent bacterial cholangitis If any of these

symptoms occur in patients with PSC, cholangiography

should be considered If a dominant stricture is found,

brush cytology samples should be obtained, although this

is an insensitive test for detecting malignant disease Often

these strictures can be dilated endoscopically with a

bal-loon catheter Some have suggested that short-term

stent-ing of dominant biliary strictures is of value in improvstent-ing

the prognosis of liver disease, whereas others have shown

that patients with biliary stents are at increased risk of

com-plications Direct surgical intervention for strictures is

sel-dom used and may predispose patients to recurrent

ascending cholangitis because of the widely patent

surgi-cal anastomosis and may make future liver transplantation

more technically demanding

Colon Cancer Patients with PSC and IBD who have

under-gone liver transplantation, as well as those without a

trans-plant, seem to be at a particularly high risk of colon cancer

if they have a remaining colon; these patients need close

screening with annual visits and colonoscopy with multiple

surveillance biopsies The detection of severe dysplasia

iden-tifies individuals who should be referred for colectomy If

liver function is well compensated and there is no

signifi-cant portal hypertension, colon surgery may be performed

before liver transplantation However, the risk of hepatic

decompensation postoperatively is high In patients with

more advanced liver disease, colectomy is best deferred until

the patient has recovered from liver transplantation

MEDICALTHERAPY ANDLIVERTRANSPLANTATION

Several drugs have been used to treat patients with PSC,

but, to date, none have been found to be useful

Penicillamine was the first drug tested in a

placebo-controlled trial, but it was ineffective Colchicine,

methotrex-ate, and ursodeoxycholic acid (UDCA) at a dose of 13 to

15 mg/kg/d have been ineffective in randomized controlled

trials Other drugs that have been evaluated in small-scale

studies, sometimes in open-label trials, have included

nico-tine, pirfenidone, pentoxifylline, and budesonide Tacrolimus

appeared to be promising in a small open-label study, but

these results must be confirmed UDCA in higher doses of

20 to 30 mg/kg/d has appeared to be the most promising,and large-scale randomized trials are being undertakenwith higher dosages of this drug

Liver Transplantation The most pressing need of patients

with PSC is for effective medical therapy for the underlyingliver disease Until this therapy is found, liver transplantation

is the only option for patients with advanced disease Thereare four chapters on liver transplantation: See Chapter 111,

“Liver Transplantation: Surgical Techniques, Including LivingDonor,” Chapter 112, “Pediatric Liver Transplantation,”Chapter 113, “Ascites and Its Complications,” and Chapter

114, “Hepatic Encephalopathy.” The results of liver plantation on patients with PSC have steadily improved; the1- and 5-year survival rates are now reported to be 90 to 97%and 85 to 88%, respectively PSC, however, may recur in theallograft, and as the follow-up period lengthens, the risk ofrecurrence seems to increase, although the recurrent diseaseseems to be mild

trans-Cholangiocarcinomas

Cholangiocarcinomas are adenocarcinomas (ACs) arisingfrom cholangiocytes, the epithelial cells lining the bile ductapparatus, and occur in approximately 8 to 13% of PSCpatients Because the biliary tree is both intrahepatic andextrahepatic, cholangiocarcinomas likewise may arisewithin the liver parenchyma or from the extrahepatic bileducts Cholangiocarcinomas arising within the hepaticparenchyma often present as intrahepatic mass lesions,whereas cancers developing along the extrahepatic ductscause mechanical biliary obstruction For reasons unex-plained, the extrahepatic ductal cholangiocarcinomas fre-quently involve the hilum of the liver, the junction of theright and left hepatic ducts These perihilar ductal cholan-giocarcinomas, therefore, frequently present with biliaryobstruction of one or both lobes of the liver Both forms

of cholangiocarcinoma may occur in PSC, although theperihilar ductal form is the most common

Clinical Presentation and Diagnosis

The clinical presentation of intrahepatic cholangiocellular

cancers is that of a liver mass Patients may present withabdominal pain, an abdominal mass, anorexia, weight loss,night sweats, and malaise or may even be asymptomatic Theserum alkaline phosphatase activity is usually elevated, butpatients are rarely jaundiced Serum tumor markers, includ-ing carcinoembryonic antigen, cancer antigen (CA) 19-9,and CA 1255, may be elevated The diagnosis of intrahep-

718 / Advanced Therapy in Gastroenterology and Liver Disease

atic cholangiocellular carcinomas is then established with a

needle biopsy specimen of a dominant liver mass showing

AC in the absence of an alternative primary lesion The

clin-ical presentation of the perihilar ductal cholangiocarcinoma

is often jaundice, pale stools, dark urine, and pruritus

Cholangitis with fever, chills, and abdominal pain is unusual

in the absence of biliary interventions A cholestatic

bio-chemical profile with unilobar bile duct obstruction is also

a common presentation The pathologic diagnosis of

duc-tal cholangiocarcinoma is more challenging because these

tumors are very desmoplastic and often extend and encircle

bile ducts in the submucosal space Endoscopic biopsies and

brushings are positive in only 40 to 70% of patients A

single-cell technique such as digitalized image analysis to assess

cel-lular aneuploidy and fluorescent in situ hybridization to

quantitate chromosomal duplication are promising

labora-tory techniques for the diagnosis of cholangiocarcinoma,

and they may double the diagnostic yield obtained with

rou-tine brush cytology In the absence of histologic

confirma-tion of cholangiocarcinoma, the diagnosis of this cancer is

often based on composite clinical rather than pathologic

cri-teria Serum CA 19-9 values greater than 100 U/L in the

absence of cholangitis are highly suggestive of

cholangio-carcinoma and may be elevated in up to 85% of patients with

this condition A computed tomographic scan, magnetic

res-onance imaging (MRI) study, or Doppler ultrasonography

showing a mass lesion and/or vascular encasement with loss

of flow in a hepatic artery or portal venous structure also is

often diagnostic In more difficult cases, positron emission

tomography with [18F]2-deoxy-D-glucose may be useful

In patients with underlying PSC, the diagnosis of

cholangiocarcinoma represents a difficult challenge The

differentiation of a dominant benign stricture from a

cholangiocarcinoma can be exceedingly difficult In this

setting, repeated biopsies and brushings over time, as well

as serial CA 19-9 measurements, are warranted In contrast

to cholangiocarcinoma in the absence of PSC, MRIs are

not helpful in this setting

Treatment

Surgery is the best option for patients with intrahepatic

cholangiocellular carcinoma Three-year survival rates of

40 to 60% have been reported in patients resected for cure

In patients with perihilar ductal cholangiocarcinoma

with-out PSC, surgical extirpation is the treatment of choice, but

surgery should be performed only with curative intent To

obtain tumor-free margins, partial hepatic resections are

often necessary In patients with tumor-free margins,

how-ever, 5-year survival rates are still only 20 to 40% and the

operative mortality is approximately 10% There is no

proven adjuvant therapy for this cancer

Surgical resection of cholangiocarcinoma in patients

with PSC is controversial Many patients with PSC and

cholangiocarcinoma have advanced liver disease with

por-tal hypertension and will not tolerate a hepatic resection.Cholangiocarcinoma in PSC is also associated with wide-spread bile duct epithelia dysplasia; hence, the risk of recur-rent de novo cholangiocarcinoma elsewhere is high In fact,the 5-year survival rate following resection for cholangio-carcinoma complicating PSC is less than 10% For patientswith cholangiocarcinoma and early PSC, liver transplan-tation is emerging as a therapeutic option

Liver Transplantation

Cholangiocarcinoma has traditionally been thought of as acontraindication to liver transplantation, but recent experi-ence from at least three centers has challenged this view Themost recent update from the Mayo Clinic reports 5-year sur-vival rates of more than 80% for patients with unresectedcholangiocarcinoma above the cystic duct without intra-hepatic or extrahepatic metastasis who underwent preoper-ative chemoirradiation therapy and exploratory laparotomybefore liver transplantation Hence, with careful protocols,patients with cholangiocarcinoma benefit from liver trans-plantation and should be examined in transplant centers

Palliative Therapies

Palliation of unresected cholangiocarcinoma includes reliefand treatment of cholestasis, although the survival rate is usu-

ally less than 1.5 years Endoscopic bile duct stenting to restore

bile flow is the usual palliative approach MRC endoscopic derivation helps make the decision as to whichlobe or segments should be stented to achieve adequate bil-iary decompression and minimize the risk of cholangitis Ifendoscopic stenting is not possible, percutaneous stents arequite successful in obtaining adequate biliary decompression

pre-Photodynamic therapy is another endoscopic palliative

approach Photodynamic therapy is accomplished by thesystemic administration of a photosensitizer that prefer-entially accumulates in malignant cells Photoactivationwith a red laser light at the time of ERCP is used to destroythe malignant cells Although a survival benefit has beensuggested in small pilot studies, a larger randomized con-trolled trial has yet to be conducted Unfortunately, there

is no proven chemotherapy for advanced disease; externalbeam radiation therapy is often employed for unresectablelocally advanced cancers

Boberg KM, Bergquist A, Mitchell S, et al Cholangiocarcinoma

in primary sclerosing cholangitis: risk factors and clinical presentation Scand J Gastroenterol 2002;37:1205–11.

Primary Sclerosing Cholangitis and Cholangiocarcinoma / 719

Broome U Management of primary sclerosing cholangitis and

its complications in adult patients Acta Gastroenterol Belg

2002;65:37–44.

Burak KW, Angulo P, Lindor KD Is there a role for liver biopsy

in primary sclerosing cholangitis? Am J Gastroenterol

2003;98:1155–8.

Chapman RW The management of primary sclerosing cholangitis.

Curr Gastroenterol Rep 2003;5:9–17.

De Vreede I, Steers JL, Burch PA, et al Prolonged disease-free

survival after orthotopic liver transplantation plus adjuvant

chemoirradiation for cholangiocarcinoma Liver Transpl

2000;6:309–16.

Gores GJ Cholangiocarcinoma: current concepts and insights Hepatology 2003;37:961–9.

Graziadei IW, Wiesner RH, Marotta PJ, et al Long-term results

of patients undergoing liver transplantation for primary sclerosing cholangitis Hepatology 1999;30:1121–7 Patel T Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States Hepatology 2000; 33:1353–7.

Peters RL, Craig JR, editors Liver pathology Contemporary issues

in surgical pathology New York: Churchill Livingstone; 1986.

Failure to initiate treatment or interruption of the essary lifelong treatment can lead to liver injury, neuro-logic and psychiatric signs and symptoms, liver failure, anddeath In patients with fulminant liver failure due toWilson’s disease or in those with advanced liver diseaseunresponsive to medical treatment, liver transplantationcan be lifesaving and curative.

nec-The age of symptomatic clinical presentation of Wilson’sdisease varies widely, but patients present mainly withhepatic or neurologic or psychiatric symptoms or signs ofdisease Liver disease typically presents earlier on, typicallywithin the first two decades of life Neurologic or psychi-atric signs and symptoms may predominate in older

Wilson’s disease is an autosomal recessive disorder of

cop-per metabolism present in approximately 1 in 30,000

indi-viduals, with disease specific mutations of the Wilson’s

disease gene, ATP7B, located on chromosome 13 In patients

with Wilson’s disease, copper accumulates to toxic levels in

the liver, brain, and other sites in the body When discovered

in a timely fashion, many of the toxic effects of copper

accu-mulation can be prevented or reversed by medical therapy

Wilson’s disease must be considered in patients below

the age of 45 years with unexplained liver disease or

cir-rhosis, and in patients with neurologic and psychiatric

symptoms and evidence of liver disease Wilson’s disease

should also be considered in those with hepatic histology

suspicious for this disorder, pediatric patients with

autoim-mune features not responsive to steroids and in those

lack-ing typical markers, patients with brain imaglack-ing

TABLE 124-1 Diagnostic Testing for Wilson’s Disease

disease Sunflower cataracts may also be seen on slit lamp exam in patients with Wilson’s disease.

of heterozygous carriers, and with severe hepatic insufficiency and in severe protein losing states Physiologically decreased in newborns; undetectable in rare patients with aceruloplasminemia.

disease.

24-hour urinary copper Normal < 50 µ g/24 h Greater than 100 µ g/24 h in most symptomatic patients and following chelation treatment; < 100 µ g in patients on

zinc therapy.

other cholestatic disorders, idiopathic copper toxicosis.

hepatocytes, pleiocytosis, and nuclear irregularities in fulminant hepatitis.

Wilson’s disease.

some asymptomatic patients.

analysis

CT = computed tomography; KF = Kayser-Fleischer; MRI = magnetic resonance imaging.

Management of Wilson’s Disease / 721

patients, but there are exceptions where these may be

sent earlier on, even under the age of 10 years, or are

pre-sent in conjunction with symptoms of liver disease

The diagnosis of Wilson’s disease is established by the

presence of KF rings and a decreased level of serum

ceruloplasmin, KF rings and neurologic or psychiatric

symptoms, and in those with liver disease and

appro-priate histology, an elevated hepatic copper (typically >

250 µg/g dry weight) Urinary copper excretion is

ele-vated above 100 µg/24 h in most symptomatic patients,

and in those with fulminant hepatic failure (FHF) due

to Wilson’s disease Genetic studies, haplotype or

poly-morphism analysis can identify affected siblings with

the caveat that the diagnosis must be first firmly

estab-lished in the proband Direct identification of ATP7B

mutations is possible, but limited by the size of the gene

and the greater than 250 disease causing mutations and

the limited availability of this testing

(http://www.uofa-medical-genetics.org/wilson/index.php) In populations

with a high frequency of specific mutations, molecular

diagnostic testing for these mutations is useful

The management of Wilson’s disease depends upon the

firm establishment of the diagnosis because treatment is

lifelong Therapy is directed at the removal of copper or

the prevention of its further accumulation in the liver and

in other body sites where it may be injurious

Treatment options for Wilson’s disease include medical

therapy with oral chelating agents or zinc, and liver

trans-plantation Dietary restrictions in copper intake are

rec-ommended along with medical therapy, especially during

the initial phase of treatment The chelating agents

peni-cillamine and trientine promote renal copper excretion and

are recommended as first line therapy for symptomatic

patients with hepatic or neurological disease These

chelat-ing agents may be used at lower dosages for maintenance

therapy Tetrathiomolybdate is an effective copper chelator

that is under investigation for initial treatment of patients

with neurologic disease Zinc functions by blocking

cop-per absorption from the gut by induction of the

endoge-nous chelator metallothionein in enterocytes Zinc is mainly

used for maintenance therapy or initial therapy for

asymp-tomatic patients, but may also have a role as an adjunct to

initial chelation therapy Liver transplantation restores a

normal phenotype with respect to copper metabolism, and

therapy specific for Wilson’s disease is no longer required

Management of Wilson’s Disease

Hepatic Disease

Patients with liver disease may be asymptomatic or they

may experience symptoms of chronic liver disease, such as

fatigue or jaundice, or manifest signs or symptoms of

por-tal hypertension, such as ascites and varices without or with

bleeding Some may have chronic hepatitis with features

indistinguishable from autoimmune hepatitis In about5%, the sudden onset of jaundice or ascites with associatedhemolysis heralds the onset of acute FHF

Patients that are asymptomatic with compensated liver

disease may be treated with zinc monotherapy or with a

chelating agent, typically trientine or penicillamine (see

Table 124-2) Tetrathiomolybdate is a very potent chelator

that may be useful for initial therapy for patients withWilson’s disease, however it is still undergoing further test-ing and is not commercially available in the United States.Patients with active disease should be treated initially with

a chelator or a chelator with zinc supplementation.Chelation therapy must be begun slowly and with carefulmonitoring for side effects Specific concerns for penicil-lamine are hypersensitivity reactions and marrow sup-pression For patients with complications of the chronicliver disease due to Wilson’s disease additional therapy isthe same as that for other chronic liver diseases The mostcommon problems are that associated with portal hyper-tension or with portosystemic shunting Patients with

ascites are treated with diuretics; those with variceal

bleed-ing are treated with β-blockers, somatostatin infusion, scopic band ligation, and portosystemic shunting, or liver transplantation Encephalopathy is present in the acute ful-

endo-minant setting, or in patients with end-stage liver disease

In this latter group, encephalopathy may exacerbate ropsychological symptoms due to the Wilson’s disease, andshould be considered and treated separately

neu-For Wilson’s disease patients with liver disease, the tial period of treatment with a chelator should range from

ini-2 to 1ini-2 months, with close monitoring maintained ing this initial period of treatment For most patients, there

dur-is a general trend towards stabilization of hepatic functionover the first 8 weeks of therapy Biochemical parameters

of hepatic inflammation and insufficiency should show atrend towards gradual improvement over the next 6 to 12months, though may improve further for up to about 4years after the initiation of treatment in some individu-als For those with ascites and edema that respond to theprimary treatment of the Wilson’s disease, requirementsfor diuretics decrease with time Similarly, the need fortreatment of encephalopathy, if necessary, may alsoimprove with primary treatment for Wilson’s disease Oncestabilization is achieved, then either the chelator can becontinued at a reduced dosage, or patients can be main-tained on zinc therapy For those individuals with severehepatic insufficiency but not fulminant liver failure due toWilson’s disease, a trial of medical therapy is warranted.However these individuals should also be followed by aliver transplantation center because some may fail torespond to therapy or suffer serious complications of theirliver disease before stabilization

Patients presenting with FHF due to Wilson’s disease ically have a nonimmune hemolytic anemia, relatively low

typ-with an interest in movement disorders can be helpful in

characterizing the degree of disability and its course

dur-ing treatment, and in assistdur-ing the patient with therapies

directed at the neurological symptoms

Psychiatric Disease

Psychiatric symptoms due to Wilson’s disease range from

behavioral changes and anxiety disorders to depression and

psychosis In very young patients, the initial manifestations

of psychiatric symptoms may be behavioral problems,

withdrawal, and difficulty concentrating or performing

higher cognitive tasks In some patients, the psychiatric

symptoms may precede any other symptoms of the disease

In adults, depression is the most commonly recognized

symptom, occurring even in treated patients There may

be components of reactive depression in some newly

diag-nosed individuals to the realization that they are afflicted

with a chronic illness or disability, or there may be no

apparent trigger for the depression The failure to

recog-nize psychiatric symptoms in patients can lead at times to

serious consequences Depression can deepen and patients

can become suicidal In some, psychosis may be severe and

require inpatient psychiatric attention

Treatment of psychiatric signs and symptoms in

patients with Wilson’s disease requires the treatment of the

underlying disease, but may also necessitate the use of

spe-cific therapies aimed at the treatment of the psychiatric

dis-order Counseling, including family counseling, may be

very helpful for some individuals The use of

pharma-cotherapy for depression, anxiety or psychosis associated

with Wilson’s disease should be guided by psychiatrists,

though initiation of therapy with antidepressants and

anx-iolytics by internists or other medical specialists while

for-mal consultation is awaited may be warranted

Prognosis

Medical treatment of asymptomatic patients prevents the

development of liver or neurologic disease The long term

survival of patients with Wilson’s disease with medical

ther-apy is excellent, even when chronic liver disease and

cirrho-sis are present at the outset Patients with cirrhocirrho-sis still maymanifest signs or symptoms due to portal hypertension,including esophageal or gastric varices or ascites In somepatients, neurologic symptoms may improve with therapy,whereas in others they may worsen during the initial phase

of treatment or patients may develop neurologic disease nolonger responsive to therapy aimed at Wilson’s disease.Liver transplantation also offers excellent survivalapproaching 90% for patients with ALF due to Wilson’sdisease, well above the survival of approximately 60% forall others transplanted for fulminant liver failure Patientswith Wilson’s disease surviving beyond 1-year post-livertransplant typically have excellent long term survival

Supplemental Reading

Brewer GJ, Dick RD, Johnson VD, et al Treatment of Wilson’s disease with zinc: XV Long-term follow-up studies J Lab Clin Med 1998;132:264–78.

Brewer GJ, Dick RD, Johnson VD, et al Treatment of Wilson’s disease with zinc XVI: treatment during the pediatric years J Lab Clin Med 2001;137:191–8.

Brewer GJ, Hedera P, Kluin KJ Treatment of Wilson’s disease with ammonium tetrathiomolybdate: III Initial therapy in a total

of 55 neurologically affected patients and follow-up with zinc therapy Arch Neurol 2003;60:379–85.

Brewer GJ, Johnson VD, Dick RD, et al Treatment of Wilson’s disease with zinc XVII: treatment during pregnancy Hepatology 2000;31:364–70.

Emre S, Atillasoy EO, Ozdemir S, et al Orthotopic liver transplantation for Wilson’s disease: a single center experience Liver Transpl 2001;72:1232–6.

Roberts EA, Schilsky ML A practice guideline on Wilson disease Hepatology 2003;37:1475–92.

Schilsky ML Wilson’s disease—genetic basis of copper toxicity and natural history In: Tavill AS, Bacon BR, editors Seminars in liver disease.Vol 16 New York: Thieme Medical Publishers Inc; 1995.

p 83–95.

Shah AB, Chernov I, Zhang HT, et al Identification and analysis

of mutations in the Wilson disease gene (ATP7B): population

frequencies, genotype-phenotype correlation, and functional analyses Am J Hum Genet 1997;61:317–28.

Sternlieb I Wilson’s disease and pregnancy Hepatology 2000;31: 531–2.

Management of Wilson’s Disease / 723

CHAPTER 125

250 persons of northern European descent The inheritancepattern of HH was originally described by Joseph Sheldon

in 1935, but the specific genetic defect went unrecognized

until 1996, when the HFE gene was cloned The HFE gene

encodes for a major histocompatibility complex class like protein, and mutations in this gene result in excessiveiron absorption and subsequent deposition in organs such

1-as the liver, pancre1-as, other endocrine organs, heart, joints,and skin (Feder et al, 1996) It is now known that the HFEprotein binds with β2-microglobulin (β2M), whichtogether interact with transferrin receptor-1, thereby affect-

ing cellular iron transport Mutations in the HFE gene alter

the cellular trafficking of HFE protein and the interactionwith β2M, resulting in inappropriate iron absorption Theexact cellular mechanism(s) by which this occurs are cur-rently being investigated (Parkkila et al, 2001)

Two major missense mutations of HFE have been

iden-tified The first mutation results in the change of the amino

acid cysteine to tyrosine at position 282 (C282Y) The second

mutation results in the change of the amino acid histidine toaspartate at position 63 (H63D) Studies have demonstratedthat approximately 85% of patients with typical HH phe-

notype are homozygous for the C282Y mutation.

Additionally, 3 to 5% of these patients are compound

het-erozygotes (C282Y/H63D) In addition to HFE-associated

HH, it is now recognized that non–HFE-associated HH can

result from mutations in other iron-related genes such as thefollowing: (1) ferroportin-1, which is involved in export ofiron across the basolateral membrane of the duodenal ente-rocyte, (2) transferrin receptor-2, which is primarilyexpressed in hepatocytes, and (3) hepcidin, which is a pep-tide synthesized in the liver that down-regulates iron absorp-tion

Historically, HH was diagnosed if patients had mal iron studies with stainable iron in hepatocytes on liverbiopsy and/or if patients had symptomatic disease withdevelopment of end-organ damage, including cirrhosis,heart failure, diabetes, arthritis, or skin pigmentation The

abnor-availability of commercial tests for the C282Y and H63D mutations of HFE provides an important diagnostic tool

in patients with iron overload (Tavill, 2001) However,recent large population studies indicate that a substantial

proportion of C282Y homozygotes do not have clinically

Iron overload is commonly seen in clinical practice and can

be divided into two distinct categories based on specific

etiology and distribution of iron loading within the liver

(Table 125-1) Primary iron overload is due to inherited

metabolic defects that result in inappropriate iron

absorp-tion relative to total body iron stores, and is termed

hered-itary hemochromatosis (HH) Iron overload not associated

with known genetic defects is called secondary iron

over-load and typically results from ineffective erythropoiesis,

hepatic diseases that predispose to associated iron loading,

and parenteral iron loading (Harrison and Bacon, 2003)

The diagnosis and management of HH will be discussed

in this summary of iron overload

The most common form of HH has an autosomal

reces-sive inheritance pattern and is found in approximately 1 in

TABLE 125-1 Iron Overload Conditions

Juvenile hemochromatosis (HFE 2)

Transferrin receptor-2 mutations (HFE 3)

Ferroportin 1 mutations (HFE 4)

Secondary Iron Overload

Acquired iron overload

Parenteral iron overload

Red blood cell transfusions

Iron-dextran injections

Long term hemodialysis

Chronic liver disease

Porphyria cutanea tarda

Hepatitis C

Hepatitis B

Alcoholic liver disease

Nonalcoholic steatohepatitis

Hereditary Hemochromatosis / 725

significant iron overload (Beutler et al, 2002) Thus, the

C282Y mutation has incomplete penetrance and additional

genetic modifiers may influence the impact of C282Y.

Clinical Features of HH

Before the advent of genetic testing, the diagnosis of HH

was based on the recognition of symptoms and physical

examination findings of iron overload Currently, most

patients with HH are detected at a much earlier stage, prior

to the development of end-organ damage, as a result of (1)

routine health maintenance examinations, which include

testing for serum iron, ferritin and liver enzymes, (2) genetic

testing of relatives of a HH patient as part of family

screen-ing, and (3) population studies of either serum iron

stud-ies or of HFE mutations When individuals are identified in

these ways, the vast majority are asymptomatic

In normal individuals, approximately 1 mg/d of dietary

iron is absorbed to maintain a total body iron storage pool

of 2 to 3 g This absorption rate maintains homeostasis,

as daily iron loss is approximately 1 mg/d In

HFE-associated HH, iron absorption is increased, with about 1.5

to 2.5 mg/d of iron being absorbed through the

duode-num Although the rate of accumulation of iron is variable

in HFE-associated HH, total iron stores of>20 g are

usu-ally required to develop symptomatic disease

Those patients who are symptomatic at the time of

diag-nosis tend to be older than 40 years of age and are

pre-dominantly male Weakness, lethargy, abdominal pain,

arthralgias, and loss of libido are common The arthropathy

seen in HFE-associated HH tends to be symmetric and

involves multiple joints Specifically, the proximal

inter-phalangeal, metacarpointer-phalangeal, wrist, knee and

verte-bral joints are most commonly involved Hepatomegaly and

cirrhosis may be present, along with skin pigmentation and

clinical diabetes.

However, patients identified through routine screening

physicals and familial screening typically are much less

symptomatic (Bacon and Sadiq, 1997) The most common

symptom in one study evaluating HH patients discovered

by familial screening was arthralgias and loss of libido The

most common clinical finding was diabetes.

Diagnosis of HH

Three groups of patients will present clinically for

evalua-tion of HH The first group includes symptomatic patients

presenting with stigmata of chronic liver disease and

ele-vated iron indices This group also includes diabetic

patients with hepatomegaly, patients with evidence of

car-diac dysfunction, skin pigmentation or sexual dysfunction,

and patients presenting with de novo sexual dysfunction

or symmetric polyarthropathy The second group

com-prises asymptomatic patients who present with abnormal

iron indices, incidentally discovered hepatomegaly, orimaging studies of the liver suggesting iron deposition Thethird group consists of first degree relatives of patients withknown HH

Blood Iron Studies

Once there is some degree of clinical suspicion or in apatient for whom screening studies are proposed, initialexamination should include a fasting transferrin satura-tion and a ferritin level A fasting serum sample is preferred

as serum iron may be elevated following meals and has adiurnal variation Transferrin saturation (TS) is calculated

by dividing the serum iron level by the total iron bindingcapacity or transferrin A TS >45% is commonly used as

a trigger for HFE mutation analysis Serum ferritin is also

helpful, but lacks specificity as it is often elevated in temic inflammatory processes The TS and ferritin are bestused in combination

sys-Genetic Testing

Genetic testing for HFE mutations should be performed

in all patients with elevated TS and ferritin as well as in first

degree relatives of patients with HFE-associated HH Those relatives determined to be homozygous for the C282Y

mutation should be carefully assessed for evidence of ironoverload Individuals who are compound heterozygotes

(C282Y/H63D) should also be examined for iron overload

and for clinical evidence of concomitant liver disease, and

a liver biopsy may be useful in these patients

in fresh or paraffin-embedded biopsy material, and the mal level is less than 1,500 µg/g dry weight Evidence sug-

nor-gests that most patients with HFE-associated HH do not

develop hepatic fibrosis until the HIC exceeds 14,000 µg/gdry weight; concomitant ethanol consumption is a poten-tiating factor in the development of cirrhosis in patientswith iron overload (Fletcher et al, 2002)

Although liver biopsy can provide useful information,

it remains an invasive test with well-documented risks.Consequently, recent studies have evaluated several clini-cal and biochemical factors in an attempt to predict the

absence of cirrhosis in patients with HFE-associated HH

726 / Advanced Therapy in Gastroenterology and Liver Disease

to obviate the need for liver biopsy It has been reported

that C282Y homozygotes with serum ferritin levels

<1000 ng/mL, with normal liver enzymes, and who are

<40 years of age are unlikely to have cirrhosis, so that liver

biopsy may be unnecessary in such patients (Bacon et al,

1999)

Treatment of Hemochromatosis

Therapy for HH is relatively simple and quite effective

Phlebotomy has been shown to effectively remove excess

iron stores without significant side effects If therapeutic

phlebotomy is started before the development of

cirrho-sis, morbidity and mortality are significantly reduced Some

clinical features of iron overload respond better to

phle-botomy than others Malaise, fatigue, abdominal pain, skin

pigmentation, and insulin requirements in diabetic patients

tend to improve, whereas arthropathy and hypogonadism

are less responsive Given these findings, early identification

and initiation of therapeutic phlebotomy should be the goal

Therapeutic phlebotomy (500 mL of blood) should be

initiated weekly with approximately 250 mg of iron

removed with each unit of blood Some patients can

tol-erate biweekly phlebotomy; in contrast, some petite older

women can only tolerate half a unit every other week The

goal should be to continue weekly phlebotomy until the

patient’s serum ferritin level is <50 ng/mL and the

trans-ferrin saturation is <50% Before each phlebotomy, the

hematocrit should be checked According to the American

Association for the Study of Liver Diseases practice

guide-lines, the hematocrit should not fall >20% with each

phle-botomy In the uncomplicated patient, each unit of blood

removed will result in a decrease in the serum ferritin level

by about 30 ng/mL This can be used as a rough guideline

to predict phlebotomy requirements to deplete excess iron

stores It is important to remember that some patients with

symptomatic HH may have in excess of 30 g of stored iron,

and thus may require several years of weekly to biweekly

phlebotomy to remove the excess stored iron The goal of

treatment is not to make patients iron deficient and/or

ane-mic, but rather to deplete excess iron stores and to achieve

serum iron values in the low normal range

Once initial therapeutic phlebotomy has been

accom-plished, maintenance phlebotomy should be performed

In most patients, one unit of blood should be removed

every 2 to 4 months with subsequent assessment of iron

status by measuring serum ferritin and transferrin

satura-tion Some patients will require more frequent

mainte-nance phlebotomies, whereas others will be on a less

frequent maintenance schedule

Occasionally, patients with significant iron loading will

present with anemia that precludes frequent phlebotomy

This rarely occurs in HH, and is more often seen in patients

with anemia due to ineffective erythropoiesis with secondary

and/or parenteral iron overload when it can be used In thesepatients, chelation therapy may be warranted Chelationtherapy with deferoxamine using continuous subcutaneousinfusion results in urinary excretion of 50 to 100 mg ironper day However, it should be noted that phlebotomyremains the easier, quicker, and less expensive therapy foriron reduction

Cirrhosis does not improve with iron reduction apy Despite therapeutic phlebotomy, hepatocellular carci-noma (HCC) continues to be a threat in patients who havecirrhosis In fact, HCC accounts for about 30% of all deaths

ther-in HH patients Orthotopic liver transplantation is a viablealternative for patients who develop decompensated liverdisease due to HH However, it is important to note that inundetected and thus untreated HH patients, the post-transplant survival rate is lower than for other types ofchronic liver disease, largely in part to increased periop-erative cardiac and infection-related complications

Family Members Screening for Hemochromatosis

All first degree relatives of patients with HFE-associated

HH should be offered screening for HH Screening of

adults should include both a genetic test for HFE

muta-tions and serum iron studies to measure fasting rin saturation and ferritin The tested relative is unlikely tohave HH if the fasting iron studies are normal and the

transfer-patient is neither homozygous for the C282Y mutation or

a compound heterozygote (C282Y/H63D) Alternatively, if the tested relative is either homozygous for the C282Y

mutation or is a compound heterozygote with an elevatedferritin or transferrin saturation, then the patient has HHand a therapeutic phlebotomy program should be initi-ated Screening of minors raises the potential for geneticdiscrimination in regards to future insurance and/or job

candidacy Therefore, it is appropriate to first perform HFE

analysis in the other parent This may obviate the need to

test the children if the other parent has no HFE mutations Family screening for HFE mutations has been shown to be

beneficial Recent studies have shown grade 3 or 4 ironstores on liver biopsies in > 25% of siblings; 10 to 15% hadsome degree of hepatic fibrosis with 3% having cirrhosis

Population

It has been suggested that population screening using

genetic testing might be ideally suited for HFE-related HH.

This is because the disorder is common, there is a longlatent phase before the development of disease manifes-tations, treatment is simple, safe, and effective and tests ofphenotypic markers are available However, it has quickly

become apparent that not all C282Y homozygotes have

phenotypic expression and this raises questions about theadvisability of large scale population screening A recentstudy by Beutler and colleagues (2002) of 41,038 subjects

from the San Diego area showed that about 25% of males

and about 50% of females who are C282Y homozygotes do

not have an elevated ferritin level This suggests that there

are large numbers of C282Y homozygotes that do not have

evidence of phenotypic expression As a result of these and

other studies, it has been suggested that population

screen-ing usscreen-ing genetic testscreen-ing may not be appropriate

Liver Disease Patients

Studies evaluating the frequency of HFE mutations and

abnormalities in iron metabolism have been done in

groups of patients with porphyria cutanea tarda (PCT),

nonalcoholic steatohepatitis (NASH), chronic hepatitis C

(HC), and alcoholic liver disease (ALD) In PCT, about half

the patients have mutations in HFE and it is well known

that this disorder responds favorably to iron reduction

therapy by phlebotomy Accordingly, all patients with PCT

should have HFE mutation analysis and serum iron

stud-ies performed In ALD, it appears that HFE mutations are

not responsible for the mild degrees of secondary iron

overload that are occasionally seen in this disorder Also,

there is no clear benefit by phlebotomy therapy in patients

who have ALD with our without abnormalities in iron

metabolism In patients with chronic HC, about a dozen

studies have been performed looking at HFE mutations

and parameters of iron metabolism Almost all studies have

shown the same prevalence of HFE mutations in patients

with HC as in control populations; some studies have

shown a relationship between increased iron and HFE

mutations, as well as in worse liver disease with increased

fibrosis At the present time, it is recommended that if iron

studies are performed in patients with HC and they are

abnormal, then HFE mutation analysis should be

consid-ered Finally, in NASH the data are mixed showing that

some groups of patients have an increased frequency of

HFE mutations and there are some data suggesting

bene-fit of phlebotomy therapy More formal and complete

stud-ies still need to be performed

Summary and Conclusions

HH is a common disorder that is increasingly being

rec-ognized in clinical practice The quality of diagnosis has

been improved with the use of genetic testing that has comeabout since the gene for hemochromatosis was discovered

in 1996 Over the last few years, we have learned that

approximately 50% of patients who are C282Y

homozy-gotes may not have evidence of phenotypic expression.Also, many other patients will have mild degrees of ironoverload Because iron overload is so easy to treat, it makessense to use phlebotomy as definitive therapy for patientseven if they have mild degrees of iron loading The use of

genetic testing (HFE mutation analysis) has superseded the use of HLA-typing in the performance of family studies

once a proband was identified, and its use in populationsurveys is still being debated Finally, the reasons for thedifferences in phenotypic expression in patients who are

genotypically identical (C282Y homozygotes) probably

relates to other genetic abnormalities identified in genesinvolved in cellular iron transport

Supplemental Reading

Bacon BR, Britton RS Hereditary hemochromatosis In: Feldman M, Friedman LS, Sleisenger MH, and Scharschmidt BF, editors Sleisenger and Fordtran’s gastrointestinal and liver disease Vol.

2 7th ed Philadelphia: Harcourt Health Sciences; 2002 p 1261–8.

Bacon BR, Olynyk JK, Brunt EM, et al HFE genotype in patients

with hemochromatosis and other liver diseases Ann Intern Med 1999;130:953–62.

Bacon BR, Sadiq SA Hereditary hemochromatosis: presentation and diagnosis in the 1990s Am J Gastroenterol 1997;92:784–9 Beutler E, Felitti VJ, Koziol JA, et al Penetrance of 845G-A (C282Y)

HFE hereditary haemochromatosis mutation in the USA Lancet

2002;359:211–8.

Feder JN, Gnirke A, Thomas W, et al A novel MHC class I-like gene

is mutated in patients with hereditary haemochromatosis Nature Genetics 1996;13:399–408.

Fletcher LM, Dixon JL, Purdie DM, et al Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemo- chromatosis Gastroenterol 2002;122:281–9.

Harrison SA, Bacon BR Herditary hemochromatosis: update for

2003 J Hepatol 2003;38:S14–23.

Parkkila S, Niemela O, Britton RS, et al Molecular aspects of iron absorption and HFE expression Gastroenterol 2001;121:1489–96 Powell LW, Subramaniam N, Yapp TR Haemochromatosis in the new millennium J Hepatol 1999;32(Suppl 1):48–62 Tavill AS Diagnosis and management of hemochromatosis Hepatology 2001;33:1321–8.

Hereditary Hemochromatosis / 727

400 grams daily Intravenous (IV) fluids should be istered to maintain a fluid intake >2 L/d Normal saline ispreferable to guard against the development of hypona-tremia, which may be caused by inappropriate secretion ofantidiuretic hormone during the acute attack.

admin-If the patient does not show improvement within 24

hours of therapy, hematin should be administered

(Mustajoki et al, 1989) Some experts in the field starthematin initially if the patient has previously had severe

acute attacks Hematin is obtained commercially as

Panhematin through Ovation Pharmaceuticals in Deerfield,

Illinois Hematin is administered over 15 to 30 minutes in

a dose of 3 to 4 mg/kg body weight IV once daily for 4 days.This usually produces a significant decline in serum andurinary levels of ALA and PBG, along with clinicalimprovement The course of therapy can be repeated if

there is not satisfactory improvement Hematin should be

given as soon as possible after dissolving in sterile waterbecause it is unstable in aqueous solution The most com-mon side effect is thrombophlebitis, which can be pre-vented by administering the solution in a large arm vein

If peripheral venous access is poor, administration should

be through a central venous catheter A mild coagulopathy

may occur during hematin therapy, but this has not caused

bleeding unless the patient is also taking on anticoagulant

The porphyrias are metabolic disorders which are

charac-terized biochemically by the increased production,

accu-mulation and excretion of porphyrins and/or porphyrin

precursors, compounds which are intermediates of the

heme biosynthetic pathway The liver and bone marrow are

the major sites of expression of the biochemical

abnor-mality The clinical manifestations are varied and include

complications for which the gastroenterologist or

hepa-tologist may be consulted for evaluation and management

Principally these occur in patients with porphyria cutanea

tarda, erythropoietic protoporphyria, and the acute

(inducible) types of porphyria Because there is a

relation-ship between the clinical manifestations and biochemical

abnormalities, the cornerstone of therapy is to use measures

which will decrease the excess production and

accumula-tion of the porphyrins and porphyrin precursors

The Acute Porphyrias

Diagnosis

Acute intermittent porphyria is the most common type

of inducible porphyria Variegate porphyria and hereditary

coproporphyria also cause acute porphyric attacks A

fourth disorder, delta-aminolevulinic acid (ALA)

dehy-drase deficiency, is very rare and is unlikely to be

encoun-tered by most physicians

Several signs and symptoms may occur during an acute

porphyric attack, reflecting widespread involvement of the

nervous system The most frequent is abdominal pain

which is caused by an autonomic neuropathy Other

fea-tures of autonomic neuropathy are tachycardia,

hyperten-sion, constipation, and urinary retention Peripheral

neuropathy may develop as the attack progresses and can

lead to paralysis in its most severe form Central nervous

system manifestations include organic brain syndrome,

depression, and seizures

The diagnosis of an acute porphyric attack is made by

demonstrating increased urinary excretion of the

por-phyrin precursors ALA and porphobilinogen (PBG) The

measurement of urinary porphyrin excretion is not used

to establish the diagnosis and may be misleading if the

excretion of the porphyrin precursors is not measured

Between attacks the diagnosis is more difficult, but in acute

The Porphyrias / 729

These problems can be avoided by reconstituting hematin

in 25% human serum albumin (Bonkovsky et al, 1991),

but this will increase the cost of therapy

Management of the signs and symptoms of the acute

por-phyric attack should be done while hematin is being given.

Pain should be controlled with acetaminophen if pain is mild,

whereas meperidine or morphine is used for more severe pain.

Hypertension and tachycardia can be treated with a β-blocker

such as propranolol Ondansetron is used to control nausea

and vomiting, and anxiety is managed with chlorpromazine

or haloperidol Seizure management may be difficult because

anticonvulsants such as barbiturates and phenytoin are major

causes of porphyric attacks Clonazepam in low doses may be

used, and gabapentin also appears to be safe Status epileptics

can be controlled with diazepam (up to 10 mg IV) or

par-aldehyde (8 to 10 mL rectally).

Many patients with acute porphyria have only a limited

number of porphyric attacks and do well if they avoid

pre-cipitating factors such as certain drugs (Moore and Hift,

1997), diminished food intake, excessive alcohol intake,

and prolonged infections Information regarding drugs and

nutrition can be obtained through the American Porphyria

Foundation However, some patients have frequent attacks,

which pose a particularly challenging problem If

recur-rent attacks in women are regularly related to the menstrual

cycle, the cautious use of oral contraceptive therapy with

ethiny estradiol is justified Alternatively, use of an analog

of luteinizing hormone releasing hormone to inhibit

gonadotropin secretion may be done The prophylactic use

of IV hematin infusions to prevent attacks should also be

considered, although available studies have shown

uncer-tain benefit If this is done, it should be noted that 100 mg

of hematin will provide 8.2 mg of iron, thus potentially

causing iron overload over an extended period of time

There are no good data regarding the effect of liver

trans-plantation in severe acute porphyria, but this may also be

a consideration Siblings and children of an individual with

acute porphyria should be screened for the disorder by

bio-chemical testing after they have reached puberty

Porphyria Cutanea Tarda

Diagnosis

The major clinical feature in porphyria cutanea tarda (PCT)

is fragility of sun-exposed skin which causes the formation

of blisters and erosions after minor trauma, particularly on

the backs of the hands Chronic skin damage may lead to

scarring and thickening of the skin which resembles

scle-roderma Skin lesions are accompanied by liver

abnormal-ities which vary from mild portal inflammation to cirrhosis

In patients with long standing untreated PCT there is an

Neurological symptoms do not occur in PCT Alcoholism

and use of estrogens are precipitating factors of PCT

Patients also have an increased prevalence of chronic tis C (HC) and mutations in the HFE gene which occur inhereditary hemochromatosis (Bloomer, 2000)

hepati-The diagnosis is established by demonstrating a marked

increase in the excretion of octacarboxyl porphyrin

(uro-porphyrin) and hepatcarboxyl porphyrin in the urine In

patients in whom the history indicates there is the ial form of PCT (10 to 20% of patients) the measurement

famil-of uroporphyrinogen decarboxylase activity in erythrocytes

may also be used to establish the diagnosis

Management

Patients with active PCT should stop the ingestion of

alco-hol, estrogens, and iron containing compounds Sun exposure

should be limited Phlebotomy is the preferred therapy

based on the observation that hepatic iron overload is mon in PCT and probably plays an important role in thepathogenesis of active disease The liver usually has anexcess of 2 to 4 g of iron, and the amount of phlebotomyneeded is on the order of 3 to 8 L of blood The schedulefor phlebotomy is to remove 500 mL of blood every 1 to 3weeks until the ferritin level is at the lower limit of normaland transferrin saturation is normal The urinary excre-tion of uroporphyrin usually decreases below 500 µg daily.This will be accompanied by an improvement in skinfragility, and patients will no longer develop blisters anderosions in sun exposed areas Chronic skin changes such

com-as scarring, hyperpigmentation, and hirtusism take muchlonger to resolve, however Approximately 10% of patientswill relapse within 1 year but usually respond to a secondcourse of phlebotomy Resumption of heavy alcohol intakeand ingestion of iron containing compounds may lead to

a recurrence of active disease and should be avoided Inwomen who had been previously treated with estrogens,there is usually not a recurrence of active disease whenestrogens are restarted Following successful therapypatients may resume normal sun exposure

For patients who do not tolerate phlebotomy, or inwhom cutaneous symptoms continue despite an adequate

course of phlebotomy, chloroquine or related compounds

is an alternative treatment These compounds appear tomobilize excess porphyrin from the liver and enhance itsexcretion in urine They should be administered in a lowdose, starting with 100 mg of hydroxychloroquine 3 times

a week and increasing to 200 mg 3 times weekly The smalldoses seldom cause eye problems Larger doses are not usedbecause they may cause significant liver damage related

to the massive removal of uroporphyrin from the liver

PCT may be particularly severe in the patient with

end-stage renal disease In this situation deferoxamine infusion

(2 to 4 g IV during hemodialysis) or small volume

phle-botomy (100 to 200 mL removed at time of hemodialysis)

along with erythropoietin therapy may be used fully Chloroquine is not used when there is renal failure

success-730 / Advanced Therapy in Gastroenterology and Liver Disease

For the patient who also has chronic HC it does not

appear that treatment of the HC is needed to manage PCT

successfully Indeed, ribavirin may potentially worsen PCT

because of increased iron absorption due to hemolysis

Thus, treatment of the HC should be delayed until the PCT

has been adequately managed, and the patient should be

monitored for recurrence of PCT if HC is subsequently

treated

Erythropoietic Protoporphyria

Diagnosis

The major clinical feature in erythropoietic protoporphyria

(EPP) is photosensitivity which usually begins in

child-hood Patients report burning, itching, swelling and

red-ness of the skin following sun exposure that varies in length

from a few minutes to several hours Some patients also

develop hepatobiliary disease because of the toxic effects

of protoporphyrin on liver structure and function In a

small number of patients, probably no more than 5%, this

may cause progressive hepatic fibrosis that leads to liver

failure and necessitates liver transplantation

The diagnosis of EPP is established in the patient with

typical photosensitivity by demonstrating an increased level

of free erythrocyte protoporphyrin Fecal protoporphyrin

excretion may also be increased Urine porphyrin levels are

normal except in the patient with liver disease, where

copro-porphyrin excretion may be secondarily increased

Management

Most sunscreens do not prevent photosensitivity in EPP

because they do not block transmission of the wavelength of

light (400 to 410 nm) which activates protoporphyrin, and

patients thus require opaque sunblocks and/or protective

clothing Ordinary window glass also does not prevent

trans-mission of this wavelength of light, but a clear film is

avail-able which can be installed on windows (including car

windows), providing protection (CLS-200-X film,

Madico,Woburn, MA) The oral intake of pharmaceutical

grade β-carotene also may ameliorate photosensitivity in EPP

Most patients increase their duration of sun exposure at least

threefold by taking 60 to 180 mg of Lumitene daily (Tishcon

Corporation,Westbury, NY) The only side effects reported

have been loose stools and the development of carotinemia

Vitamin A toxicity does not occur

For the patient with EPP in whom liver disease develops,

therapeutic approaches are used to diminish the production

of excess protoporphyrin, and interrupt its enterohepatic

circulation Correction of iron deficiency may dramatically

reduce the erythrocyte protoporphyrin level, although iron

therapy has caused worsening of EPP in some patients

Transfusion with red cells and the IV administration of

hematin have also diminished erythrocyte protoporphyrin

levels, presumably through an effect on the bone marrow

Oral administration of cholestyramine (8 to 12 g daily) may

be used to interrupt the enterohepatic circulation of porphyrin and thereby reduce the amount of protopor-phyrin which the liver is required to excrete Drugs whichhave a potentially cholestatic effect should be stopped

proto-Ursodiol may be administered to enhance the secretion of

protoporphyrin into bile, but this must be done cautiouslybecause ursodiol does not solubilize protoporphyrin in bile.Patients with advanced liver disease should be consid-

ered for liver transplantation They are also susceptible to

a crisis which is characterized by abrupt worsening of liverchemistries and the erythrocyte protoporphyrin level,severe abdominal pain that often radiates into the back,mild hypertension, and tachycardia These symptoms arefelt to be caused by the neurotoxic effect of protoporphyrinwhen high blood levels are reached The crisis may be sta-

bilized and reversed by the combination of

plasmaphore-sis and hematin administration A 1.5 to 2.0 volume

plasmaphoresis should be done 3 times weekly, followingeach plasmaphoresis with the intravenous administration

of hematin in a dose of 3 to 4 mg/kg body weight Duringthe peri-operative transplant period the patient is suscep-tible to a number of unique problems because of the highblood and tissue levels of protoporphyrin Photodamage

to the skin and abdominal tissue may occur during sure to fluorescent lights in the operating rooms, whichshould be covered with CLS-200-X film Skin and abdom-inal organs should also be protected from light as much aspossible during the operation Transfusion with red cellsshould be minimized because transfused red cells are sen-sitive to photohemolysis caused by circulating protopor-phyrin Axonal neuropathy has also occured in theimmediate postoperative period and causes severe motorweakness that necessitates prolonged mechanical ventila-tion Nevertheless, liver transplantation has been success-ful in the majority of patients with EPP, and the 5-yearsurvival of patients has been good (Bloomer et al, 2000).Unfortunately, liver transplantation does not significantlyalter the bone marrow production of protoporphyrin, andpatients may develop protoporphyrin induced damage inthe graft as time progresses Bone marrow transplantation

expo-in such patients should be considered as this will changethe EPP phenotype (Poh-Fitzpatrick et al, 2002)

Philadelphia: Lippincott Wiliams and Wilkins; 2003 p.

1231–60.

Bloomer JR, Rank JM, Payne WD, et al Follow-up after liver

transplantation for protoporphyric liver disease Liver Transpl

Surg 1996;2:269–75.

Bonkovsky HL, Healey JF, Lourie AN, et al Intravenous

heme-albumin in acute intermittent porphyria: evidence for

repletion of hepatic hemoproteins and regulatory heme pools.

Am J Gastro 1991;86:1050–6.

Moore MR, Hift RJ Drugs in the acute porphyrias—toxicogenetic

diseases Cell Mol Biol 1997;43:89–94.

Mustajoki P, Tenhunen R, Pierach C, et al Heme in the treatment

of porphyrias and hematological disorders Sem Hematol 1989;26:1–9.

Poh-Fitzpatrick MB, Wang X, Anderson KE, et al Recessive erythropoietic protoporphyria: altered phenotype after bone marrow transplantation J Am Acad Dermatol 2002;46:861–6 Rocchi E, Gibertini P, Cassanelli M, et al Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda J Lab Clinc Med 1986;107:36–42 The porphyrias Sem Liver Dis 1998; 18:1–101.

The Porphyrias / 731

CHAPTER 127

phases) The gold standard for the diagnosis of HCCremains the pathologic confirmation by histology or cytol-ogy However, because of risks of needle track-seeding andimprovements in hepatic imaging, noninvasive criteria havebeen developed for the diagnosis of HCC in patients withcirrhosis (Table 127-1) The United Network of OrganSharing (UNOS) accepts listing of patients with HCC based

on the following criteria: a vascular lesion on spiral CT ordynamic MRI plus one of (1) pathological confirmation,(2) AFP>200 ng/mL, or (3) confirmation of vascular mass

Hepatic tumors may originate from liver tissue, including

from the hepatocytes, bile duct epithelium, or

mesenchy-mal tissue, or spread to the liver from primary lesions in

other organs In this chapter we will concentrate on

hepa-tocellular carcinoma (HCC) and cholangiocarcinoma, the

most common primary hepatic neoplasms

HCC

HCC is currently the fourth most common tumor

world-wide Once thought to be rare in the United States, the

inci-dence of HCC has risen from 2.2 per 100,000 persons in

1990 to 3 per 100,000 persons in 1996 to 1998, an increase

of 25% during the last 10 years (Davila et al, 2003) Chronic

hepatitis C infection has been shown to be the most

impor-tant factor for the increase in incidence of HCC in the

United States, Europe and Japan, whereas chronic hepatitis

B infection is the most important etiologic agent

world-wide Cirrhosis remains the most important risk factor for

the development of HCC regardless of the etiology, with

5-year probability of developing HCC among cirrhotics

around 20% Thus, cirrhotic patients, particularly those

with Child-Pugh class A and B, are the target population

for surveillance for HCC Patients with Child class C

cir-rhosis should be considered for liver transplantation so the

impact of HCC surveillance on survival is less clear, except

in the context of ranking on the transplantation waiting list

The current recommendation for HCC surveillance is to

perform α-fetoprotein (AFP) measurement and hepatic

ultrasonography every 6 months The best recall policy

deter-mined at a recent consensus conference is depicted in Figure

127-1 (Bruix et al, 2001) The level of AFP that should

trig-ger a workup to detect HCC is controversial, but most

inves-tigators will initiate radiologic investigations when the AFP

value exceeds 20 ng/mL Because of the difficulty in

detect-ing small tumor nodules in a cirrhotic liver, dynamic

mag-netic resonance imaging (MRI) or computed tomography

(CT) is preferred to ultrasound (US) in evaluating elevated

AFP values MRI is in general slightly more sensitive and

spe-cific than CT scan for the evaluation of HCC (Semelka et al,

2001) One important technique to improve the sensitivity

of CTs and MRIs in the detection of HCC is dynamic

triple-phase scanning (arterial, portovenous, and venous delayed

Cirrhotic patients (US+AFP/gm)

Liver nodule

Spinal CT US/3 m

AFP ≥ 400ng/mL CT/MRI/Angiography

Normal AFP**

≥ 2 cm

FNAB

* Available for curative treatments if diagnosed with HCC

** AFP levels to be defined

***Pathological confirmation or noninvasive criteria (Table 127-1)

> 2 cm

No nodule

No HCC

FIGURE 127-1 Surveillance and recall strategy for hepatocellular

carcinoma Reproduced with permission from Bruix J et al, 2001 AFP = α -fetoprotein; CT = computed tomography; HCC = hepatocellu- lar cancer; US = ultrasound

TABLE 127-1 Definition of Hepatocellular Carcinoma Based on the 2001 EASL Consensus Conference

A Histology

B Noninvasive Criteria Two imaging* techniques showing a lesion of > 2 cm with arterial hypervascularization

One imaging technique showing a lesion of > 2cm with arterial

hypervascularization plus AFP > 400 ng/mL

AFP = α -fetoprotein.

*Four techniques, including ultrasound angiography, spiral computed tomography, dynamic netic resonance imaging, and angiography.

mag-Primary Hepatic Neoplasms / 733

by angiogram, chemoembolization or ablation of the lesion

Currently none of the staging systems for HCC is able to

stratify patients according to their predicted survival or help

determine the best treatment option In the United States,

most liver centers follow UNOS TNM staging as liver

trans-plantation is the best treatment of HCC

Treatment

Great advances have been made with regards to the

treat-ment of HCC Treattreat-ment can be divided into effective

(potentially curative) or palliative interventions Effective

therapies include tumor resection, orthotopic liver

trans-plantation (OLT), and ablative techniques, all of which offer

the hope of achieving a long term response and, thereby,

improving survival However, only about 30% of patients

with HCC will be diagnosed at a stage when effective

treat-ment can be applied; the remaining 70% will only be

eli-gible for palliative interventions Palliative therapies are

those that aim to prolong survival but evidence supporting

improvement in survival is lacking for most of these

ther-apies Palliative therapies for HCC include intra-arterial

chemoembolization, radiation, and systemic

chemother-apy What follows is a review of the efficacy of the

avail-able treatment options

LIVERTRANSPLANTATIONOLT is theoretically the best treatment option for HCC

because it removes the tumor together with the entire

dis-eased liver, thereby eliminating the risk for development

of de novo HCC In the early 1990s the results of OLT for

HCC were dismal with 1-year survival of 10 to 70% and

3-year recurrence rates up to 69% In 1996, Mazzaferro and

colleagues published a seminal paper on OLT for HCC By

restricting OLT to patients with a single tumor 5 cm or less,

and no more than 3 tumors each less than 3 cm in ter, the 4-year actuarial survival rate was 75% and

diame-recurrence-free survival was 83% At transplantation, somepatients were found to have tumors that exceeded therestrictive criteria Of the 35 (73%) patients that met thepredefined criteria, the overall and recurrence-free survivalswere 85% and 92%, respectively, whereas in the 13 patients(27%) that had tumors exceeding the criteria the overallsurvival was 50% and recurrence-free survival was 59%.These criteria have been adopted by UNOS Table 127-2summarizes the findings of major studies assessing OLTfor HCC With 5-year survival around 60 to 75%, theresults of OLT for HCC are close to that of OLT for non-HCC patients

However, OLT has several drawbacks Not all patientswith HCC can afford or have access to liver transplanta-tion In addition, waiting time for liver transplantation isincreasing worldwide from 6 months to more than 1 year.Therefore, some patients will not be able to proceed to OLTbecause of tumor progression or deterioration in medicalcondition A recent study from Barcelona (Llovet et al,2002) showed a decrease in survival from 84 to 54% as thewaiting time to OLT increased from 62 to 162 days In theUnited States, patients with HCC receive higher rankingscores to shorten their waiting time and to prioritize them.The impact of the adjusted score on the posttransplant sur-vival of HCC patients and the wait-list mortality of patientswith end-stage liver disease and no HCC remains to bedetermined

The size limitations described by Mazzaferro and leagues (1996) have been challenged The group in SanFrancisco (Yao et al, 2001) reported 1- and 5-year survival

col-of 90% and 75%, respectively, among 70 patients going OLT for HCC including 25% with solitary tumors

under-5 to 6.under-5 cm in diameter or <3 tumor nodules each <4.5 cm

TABLE 127-2 A Summary of Studies Comparing the Outcome of Patients Undergoing Liver Transplantation or Surgical Resection for Hepatocellular Carcinoma

734 / Advanced Therapy in Gastroenterology and Liver Disease

with a total diameter <8 cm The authors suggested

loos-ening the criteria of OLT for HCC, but these results should

be confirmed by other centers before changing the current

criteria

Live donor transplantation can potentially eliminate the

significant waiting time and allow the surgery to be

per-formed electively A recent case series from Japan described

56 patients who underwent live donor transplantation for

HCC The 1- and 3-year survival rates were 73% and 55%,

respectively, and 6 tumor recurrences were noted The

authors stated that the 3-year survival rate was lower than

that in patients who underwent live donor transplantation

for nonmalignant liver disease (73%) However, in this

study 35% of the patients had tumors that exceeded the

Mazzaferro criteria, which likely led to the poor results A

national study is needed to determine the safety and

effi-cacy of live donor transplantation for HCC in the United

States

SURGICALRESECTIONResection is second to OLT in effectiveness as a treatment

of HCC Its main disadvantages are the high recurrence

rates because it does not remove the diseased liver that lead

to the development of HCC, and it does not improve the

overall liver function In addition, surgical resection is

fea-sible only in patients with preserved hepatic function Table

127-2 summarizes the long term results of resection

com-pared with OLT Patient selection is of outmost importance

in order to achieve a long term response In selected

indi-viduals with Child’s class A cirrhosis, who have normal

bilirubin level and no portal hypertension by hepatic

venous pressure measurements, the 5-year survival reaches

50% A recent study showed that Child’s class A patients

with single tumor nodule and a preoperative aspartate

aminotransferase <2 times the upper limit of normal were

independent predictors of no recurrence after resection In

these excellent candidates, the decision to perform liver

transplantation or resection depends on the local resources,expertise, and organ availability In most series of surgicalresection for HCC recurrence rates of 50% at 3 years and70% at 5 years were reported making resection an unat-tractive option to many patients However, in patients withHCC and no cirrhosis liver resection is the best option Aseries of 68 noncirrhotic patients from France who under-went resection for HCC with a mean tumor diameter of8.8 cm showed a survival of 40% and 26% at 5 and 10years, respectively (Bismuth et al, 1995) In Western coun-tries where the overwhelming majority of HCC patientshave cirrhosis, resection will remain the second option aftertransplantation The availability of live donor transplan-tation may shift some HCC patients towards transplanta-tion that otherwise would undergo surgical resection

LOCALABLATIONLocal ablation of HCC is usually performed while patientsawait liver transplantation or as a curative treatment inpatients with one or a few small tumor nodules but whoare not candidates for surgical intervention because ofother medical comorbidities Ablation may be accom-

plished by chemical (eg, 100% ethanol or 50% acetic acid)

or physical (eg, radiofrequency, cryoablation, or microwave)

techniques Table 127-3 summarizes the studies involvingthe more common methods for percutaneous ablation.Ethanol ablation has been the most widely used technique.The procedure is safe and is performed under US guidanceand conscious sedation The long term outcome afterethanol injection was compared with surgical resection in

a European study A cohort of 30 patients underwent cutaneous ethanol injection and another cohort of 33 con-temporary patients underwent surgical resection Thesurvival rates were similar among the 2 groups, with 81%and 44% at 1 and 4 years for resection, and 83% and 34%,respectively, for ethanol injection However, a mean of 4.8sessions were required for complete ethanol ablation Even

per-TABLE 127-3 A Comparison of the Outcome of Local Ablative Techniques for Hepatocellular Carcinoma

-*Maximal tumor diameter.

Microwave = percutaneous microwave coagulation; PEI = percutaneous ethanol injection; RFA= radiofrequency ablation.

though the groups were not comparable (resection patients

were all Child’s class A), this study showed for the first time

that percutaneous ablation achieved similar survival to

hepatic resection (Castells et al, 1993)

Radiofrequency ablation (RFA) is a relatively new

tech-nique compared to ethanol injection Its ability to destroy

HCC tissue at one session, its tolerability and the paucity

of side effects make it the preferred local ablative therapy

in many liver centers The principle of RFA involves

insert-ing an insulated cannula into the tumor where alternatinsert-ing

current is passed, resulting in heating of the area around

the tumor to about 100°C The cannula contains about 8

to 10 individual electrodes that when deployed within the

tumor allow a sphere of up to 5 cm diameter to be

destroyed As seen in Table 127-3, RFA for HCC has

achieved comparable survival and recurrence rates to

sur-gical resection and ethanol injection Table 127-4 shows

the 3 studies that have directly compared radiofrequency

ablation versus ethanol injection in patients with tumors

<5 cm RFA was more efficient at achieving complete

abla-tion, 90 to 100% compared with 80 to 94% for ethanol,

with fewer sessions The largest study by Lencioni and

col-leagues (2003) also showed a better 2-year overall survival

for RFA of 98% versus 88%, and a better recurrence-free

survival of 96% versus 62% Thus, RFA outperforms

ethanol injection for the treatment of HCC less than 5 cm

in maximal diameter

Microwave, acetic acid injection and cryoablation have

also been performed to ablate HCC As seen in Table

127-3, microwave ablation can achieve complete coagulative

necrosis in up to 90% of patients with 3-year survival rates

of 73% One study compared microwave coagulation with

RFA of lesions less than 3 cm; complete necrosis was

achieved in 96% of those who underwent RFA versus 89%

in those with microwave coagulation (p = 26); RFA

required less sessions for tumor ablation (1.1 versus 2.5

[p<.001])

The risks involved with ablation techniques include

puncture site bleeding, fever, abdominal pain, and

tran-sient elevations of the aminotransferases Both RFA and

ethanol injection have been associated with needle

track-seeding of tumors, especially when the lesions are >2cm

A recent report from Italy examined the safety of RFA in2,320 HCC patients with 3,554 lesions of 3.1±1.1 cm inmaximal tumor diameter A total of 6 (0.3%) patients diedfrom complications related to the procedure includingintestinal perforation (2), peritonitis (1), massive tumorhemorrhage (1), biliary strictures (1), and one unknown

An additional 50 patients (2.2%) had major complications,such as peritoneal hemorrhage, neoplastic seeding, intra-hepatic abscess, and intestinal perforation The authorsconcluded that RFA is a well tolerated and safe procedurefor the treatment of HCC

Ablative therapies are safe and effective at achievingtumor necrosis However, the high recurrence rates at 3 and

5 years and the development of de novo tumors indicatethat this is not a cure for most patients Local ablative ther-apy is most effective for lesions <3 cm diameter, althoughsome studies found that complete ablation can be achievedwith tumors up to 5 cm diameter Local ablation is bestsuited for patients with no more than 2 to 3 tumor nod-ules Among the various techniques, RFA and ethanolinjection have been more extensively studied Both tech-niques are similar in efficacy and safety RFA has the advan-tage that tumor ablation can be achieved in fewer sessionsand has been shown to improve survival in randomizedclinical trials compared with ethanol injection The mainadvantages of ethanol injection are low cost and ease of thetechnique However, the disadvantages include the require-ment of multiple sessions, and changes in echo features

of the tumor after the initial injection make subsequentvisualization of the tumor more difficult The choice ofablative technique to be used for HCC will depend on thelocal expertise

INTRA-ARTERIALCHEMOEMBOLIZATIONHCC is a vascular tumor that derives its blood supply fromthe hepatic artery, whereas the rest of the liver is perfused byboth hepatic artery and portal vein Therefore, selectiveintra-arterial administration of chemotherapeutic agentsfollowed by embolization of the major tumor artery has been

TABLE 127-4 Randomized Controlled Trials Comparing Percutaneous Ethanol Injection and Radiofrequency Ablation

All studies included patients with a maximal tumor diameter < 5 cm

*1-year recurrence rate;

† 2-year recurrence-free survival;

‡ 2-year survival

PEI = percutaneous ethanol injection; RFA = radiofrequency ablation.

Primary Hepatic Neoplasms / 735

736 / Advanced Therapy in Gastroenterology and Liver Disease

performed to treat HCC This procedure may be

compli-cated by liver failure possibly due to ischemic infarct of

adja-cent nontumorous liver A metanalysis evaluating the impact

of arterial embolization and arterial chemoembolization was

performed (Llovet and Bruix, 2003) There was a survival

benefit with chemoembolization versus control, but no

sur-vival benefit with embolization alone versus control A recent

randomized study compared chemoembolization versus

embolization alone with supportive care in 112 patients with

unresectable HCC (Llovet et al, 2002) The groups were

equally matched and two-thirds of the patients had

multi-nodular tumors with a maximal tumor diameter of about

5 cm Only chemoembolization showed a survival benefit

compared to conservative treatment (hazard ratio 0.47; 95%

CI 0.25 to 0.91) The tumor-free survival at 2 years was 63%

for chemoembolization, 50% for embolization, and 27% for

conservative management These studies showed that in

carefully selected patients with compensated or mildly

decompensated liver function (78% Child’s A and 22%

Child’s B), absence of tumor-related symptoms, renal

fail-ure or portal vein invasion and a maximal tumor diameter

of about 5 cm, intra-arterial chemoembolization can lead to

a survival benefit However, patients with lesions of about

5 cm are also eligible for local ablation Therefore, local

expertise and underlying liver function will dictate whether

patients with small HCC (<5 cm) will undergo

chemoem-bolization or ablative techniques

SYSTEMICCHEMOTHERAPY/RADIATION/HORMONALTHERAPY

A variety of chemotherapeutic regimens have been used

for patients with HCC not amenable to any of the

treat-ments discussed previously The results have been dismal

and may in part be elated to the limitations in choice of

chemotherapeutic agents and the dose that can be used in

patients have underlying cirrhosis Focal liver radiation

targeted to the tumor has been shown to result in

com-plete responses in 17 to 92% of unresectable HCC but is

most effective in smaller (<7 cm) lesions However, about

one-third of patients develop radiation induced liver

dam-age, which may lead to hepatic decompensation There

have been no randomized control trials comparing

radi-ation against local ablradi-ation or chemotherapy A new form

of radiation therapy is direct intratumoral injection of90Y

spheres, has been reported to result in complete

destruc-tion of nonresectable HCC This technique needs to be

further evaluated in randomized clinical trials Three large

double-blind randomized clinical trials have shown no

benefit for tamoxifen in HCC (Bruix et al, 2001)

Antiangiogenic agents have also shown promise in pilot

trials, but studies in larger number of patients in

com-parison to other established therapies are needed to

deter-mine the role of antiangiogenic agents in the treatment of

HCC

Summary

The incidence of HCC is rising in the United States likelydue to the hepatitis C epidemic Surveillance should be per-formed in patients with cirrhosis given that there are effec-tive therapies, such as liver transplantation, resection andablation that may achieve longterm survival Figure 127 2shows an algorithm for the treatment of patients withHCC The choice of therapy is dependent on the extent ofthe tumor, the underlying liver function, general medicalcondition of the patient, and local expertise

Cholangiocarcinoma

Three epidemiologic studies have shown an increase in theincidence of cholangiocarcinoma in the United States Theincidence is about 8 per million (1973 to 1997) with one-third being intrahepatic cholangiocellular cancers and two-thirds ductal cholangiocarcinomas (Gores, 2003) Thelifetime risk for developing cholangiocarcinoma in patientswith primary sclerosing cholangitis (PSC) is approximately1.5% per year of disease A TNM pathologic staging hasbeen developed but is of little clinical value Figure 127-3shows the algorithm for examining a patient suspected ofhaving a malignant stricture or cholangiocarcinoma.Surgery is the best treatment option for patients with intra-hepatic cholangiocarcinoma, with 3-year survival ratesclose to 60% However, only about 10% of these patientswill be eligible for surgical interventions For patients withductal cholangiocarcinoma, surgical extirpation should beperformed with a curative intent and partial hepatic resec-tion is often necessary In patients with tumor-free mar-gins, the 5-year survival rates are only 20 to 40%, and theoperative mortality is approximately 10% There is noproven adjuvant therapy Surgical resection of cholangio-

Solitary Lesion

Resection

Involvement Metastasis

No Portal HTN

OLT

Awaiting OLT:

Ablation TACE

Transplant Candidate?

No Yes

Ablation TACE

TACE Radiation Chemotherapy Novel Agents

Comfort care Hepatocellular Carcinoma

FIGURE 127-2 Algorithm for the treatment of hepatocellular

car-cinoma OLT = orthotopic liver transplantation; TACE = transarterial chemoembolization.