TITLE: INTRAHEPATIC CHOLESTATIC LIVER DISEASE
AUTHOR: DAVID S. BARNES, MD -- Department of Gastroenterology and Hepatology
PUBLISHED: JULY 9, 2002
     
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The term cholestasis originally derives from Greek and literally means "a standing still of bile." This disruption of bile flow can occur on a cellular level in the hepatocyte, at the level of the intrahepatic biliary ductules or from an extrahepatic mechanical obstruction of the bile ducts. Frequently, bile flow is only partially disrupted giving rise to "anicteric cholestasis"—cholestasis without jaundice. Cholestasis is defined, therefore, both clinically and biochemically with varying degrees of jaundice, pruritus and elevated levels of conjugated bilirubin, alkaline phosphatase, gamma-glutamyltranspeptidase, 5 prime nucleotidase, bile acids, and cholesterol. A conventional categorization of cholestatic liver diseases divides them into intrahepatic or extrahepatic causes (Table 1).

This chapter covers the different types of intrahepatic cholestatic liver disease. A separate chapter on gallbladder and biliary tract disease is accessible by a link on the right-hand side of this page.
PRIMARY BILIARY CIRRHOSIS
DEFINITION

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease predominantly affecting middle-aged women. It is presumed to be an autoimmune disease caused by chronic destruction of the small intrahepatic bile ducts.

PREVALENCE
PBC is most commonly diagnosed after the age of 40. Ninety percent of patients with PBC are female. Prevalence is higher among northern European population groups and lower in Japan. Disease prevalence estimates range from 19 to 150 cases per million population with an incidence between 4 and 30 cases per million per year.1
PATHOPHYSIOLOGY

PBC is considered an autoimmune disease with immune destruction of the interlobular bile ducts resulting in a gradual progressive ductopenia. Over time, this leads to fibrosis, cirrhosis, and liver failure. It is hypothesized that the autoimmune response is a T cell-mediated immune response against biliary epithelial cells with direct cytotoxicity or lymphokine-mediated cell damage.

SIGNS AND SYMPTOMS

With the ready availability of automated blood chemistry testing, many patients are diagnosed with PBC in an asymptomatic phase. The most common initial symptom is fatigue, which occurs in 70% to 80% of patients. Fatigue does not necessarily correlate with the severity of disease but can be associated with a sleep disorder and depression. Pruritus is also a common symptom, occurring in 50% to 60% of patients. As the disease progresses, patients may develop symptoms of portal hypertension such as variceal hemorrhage and ascites. Xanthomata, particularly around the eyes (xanthelasma) are commonly found in patients with PBC. PBC is also associated with metabolic bone disease resulting in premature osteoporosis. As the disease progresses, there can be fat-soluble vitamin malabsorption due to a decrease in biliary secretion of bile acids. There is an increase in other autoimmune disorders in patients with PBC including autoimmune thyroid disease, sicca syndrome, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, and telangiectasia), celiac disease, and inflammatory bowel disease.
DIAGNOSIS

The diagnosis of PBC is based on a combination of findings including cholestatic liver enzymes, a positive antimitochondrial antibody (AMA), and characteristic liver biopsy findings. Elevated serum alkaline phosphatase of liver origin is the most common laboratory finding. The most characteristic laboratory finding in PBC is the presence of the AMA, generally in a titer of 1:40 or greater. Greater than 95% of patients with PBC will have a positive AMA. The liver biopsy findings include portal hepatitis with granulomatous destruction of bile ducts. The histologic changes are divided into 4 stages; ranging from stage 1, characterized by portal inflammation and bile duct destruction, through stage 4, characterized by histologic cirrhosis. Overlapping stages can be found in an individual patient.

A subgroup of patients have a positive AMA with normal liver enzymes. The majority of these patients ultimately develop biochemical evidence of cholestasis and symptomatic disease. Another subgroup of patients with cholestasis and histology suggestive of PBC are AMA-negative, so-called "AMA-negative PBC".2 The natural history of AMA-positive and AMA-negative PBC appears to be similar. Finally, a positive AMA, usually in low titer can be seen in patients with a variety of other autoimmune disorders.3
THERAPY

Treatment of PBC is directed at both the underlying disease and its side effects. Ursodeoxycholic acid (UDCA) is a dihydroxy bile acid that is hydrophilic and nonhepatotoxic. Several large randomized trials using UDCA show biochemical improvement.4-8 There is not universal agreement that UDCA therapy slows the progression of PBC. It is currently the accepted treatment of choice at a dose of 13 to 15 mg/kg daily, either in divided doses or as a single daily dose.9 Other drugs currently under consideration for treatment, but without sufficient data to support their use, include methotrexate and oral budesonide. Liver transplantation is recommended for patients with decompensated liver disease.

The most common symptom of PBC requiring treatment is pruritus. First-line treatment consists of cholestyramine at a dose of 4 gm daily up to 16 gm daily. At least 4 hours should lapse between taking cholestyramine and any other medication. Rifampicin 300-600 mg per day is second-line treatment for pruritus in patients who do not respond to cholestyramine. Opioid antagonists such as naltrexone have also been used in treatment-resistant cases, as has plasmapheresis.

Other recommendations include:

  1. Patients with stage IV PBC may develop portal hypertension and should be screened for the presence of esophageal varices when first diagnosed and every 3 years after that. If prominent varices are found, consider primary prophylaxis (pharmacologic or endoscopic).
  2. Bone mineral density should be assessed at the time of diagnosis and periodically thereafter. Hormone replacement therapy is recommended where appropriate. Although transdermal estrogen preparations are available, no studies have shown their superiority to oral estrogen in terms of therapeutic efficacy or hepatic side effects. If osteoporosis is present, consider treatment with a bisphosphonate.
  3. Fat-soluble vitamin deficiency should be considered in patients with hyperbilirubinemia and oral replacement may be necessary.
  4. The association of thyroid disease with PBC has led to the recommendation of checking a serum thyroid stimulating hormone at the time of diagnosis and periodically thereafter.
    5.
OUTCOMES

PBC is generally a progressive disease although there are reports of prolonged survival with minimal progression of disease. Patients who are asymptomatic at presentation have a longer survival than those people who are symptomatic; however, their survival appears to be shorter than an age-matched controlled population. About one third of patients who are asymptomatic at presentation will become symptomatic within 5 years. Symptomatic patients have an 8-year survival of approximately 50%. Survival models have been developed to more precisely predict outcome and are useful in timing for liver transplantation.
NATIONAL GUIDELINES
"The National Guidelines on the Management of Primary Biliary Cirrhosis" have been published and are available online (www.aasld.org).9 This is a comprehensive review of PBC with discussions on diagnosis, clinical manifestations, associated conditions and therapy. Recommendations made in the review are judged on the quality of evidence in the medical literature used to formulate each guideline.
PRIMARY SCLEROSING CHOLANGITIS
DEFINITION
Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic liver disease resulting from inflammation, fibrosis, and destruction of the intra- and extrahepatic bile ducts. This leads to multiple areas of stricturing in the biliary tree and eventually to cirrhosis.
PREVALENCE
The estimated prevalence of PSC is 20 to 60 cases per 1 million people. There is a 2:1 male predominance. Approximately 70% of patients with PSC will have inflammatory bowel disease, more commonly ulcerative colitis than Crohn's disease.10
PATHOPHYSIOLOGY
The pathophysiology of PSC is unclear, but there is evidence suggesting an autoimmune component to the disease. There is also a genetic predisposition with an increased prevalence of HLAB2 and DR3 in patients with PSC. Other proposed etiologies include chronic portal bacteremia, cytotoxic bile acids, and viral infections. The periductal inflammation leads to progressive multifocal stricturing of the intra- and extrahepatic biliary tree.10
SIGNS AND SYMPTOMS
It is quite common for patients with PSC to be asymptomatic. In one large study, only 56% of patients had one or more symptoms at the time of initial diagnosis.11 The most common symptom is fatigue which is nonspecific. Other less common symptoms include pruritus, weight loss, and fever. Occasionally, patients present with symptoms of portal hypertension including the onset of ascites or variceal bleeding, or symptoms of bacterial cholangitis. Physical examination at initial presentation may be normal, although jaundice and hepatosplenomegaly may be present in up to 50% of patients.
DIAGNOSIS

The diagnostic test of choice for PSC is cholangiography typically an endoscopic retrograde cholangiogram (ERC). Occasionally, percutaneous transhepatic cholangiogram is necessary to establish the diagnosis when ERC is unsuccessful. The cholangiogram typically shows multiple strictures of the intra- and extrahepatic biliary tree. In one large study, 27% of patients had intrahepatic ductal involvement only and 6% had only extrahepatic ductal changes.11 Magnetic resonance cholangiogram (MRC) has also been used in the diagnosis of PSC. When compared to ERC in a recent study MRC had a sensitivity of 85-88% and a specific of 92-97% with good interobserver agreement.12 It remains to be seen if MRC will surpass ERC as the first line test for diagnosis of PSC.

Liver biopsy is not diagnostic for PSC but findings often include the absence of intralobular bile ducts (ductopenia), bile duct proliferation, and periductal fibrosis with an onion-skin fibrosis and nodular fibrous scars. Liver enzymes typically show an elevated alkaline phosphatase of biliary origin although there is a subgroup of patients with early PSC who present with a normal alkaline phosphatase.

THERAPY

Currently, no medical therapy has been shown to be clearly beneficial in PSC.13 Ursodeoxycholic acid (UDCA) has been shown in small studies to improve symptoms and biochemical tests. In a two year randomized controlled trial using UDCA at 12-15 mg/kg/day, however, no beneficial effect on survival, liver histology, cholangiographic appearance, or symptoms was found.14 A small randomized trial of 26 patients using "high-dose" UDCA (20 mg/kg/day) showed possible benefit in cholangiographic appearance and fibrosis, but larger studies are needed before routine use of "high-dose" UDCA can be recommended.15 Medical management of PSC is therefore limited to complications that arise during the course of the disease. These complications and treatment are similar to those listed above for the management of PBC.

Up to 20% of patients with PSC will develop jaundice and/or cholangitis caused by a dominant stricture of the biliary tree, which can be treated with balloon dilatation with or without the placement of a biliary stent.13 This is typically done endoscopically, but can be done percutaneously.

Liver transplantation is effective for patients who have evidence of end-stage liver disease or who have recurrent bouts of cholangitis that cannot be controlled with dilation of a dominant stricture.
OUTCOMES
PSC is a progressive disease often leading to biliary cirrhosis within 10 to 15 years. Patients who are asymptomatic at the time of diagnosis fare better than those who are symptomatic, but the disease tends to progress in either case. The average overall survival time is approximately 10 years from the date of diagnosis.

Cholangiocarcinoma is a dreaded complication of PSC, occurring in 4% to 20% of patients or even higher in autopsy studies. The development of cholangiocarcinoma is often accompanied by clinical decline but can be difficult to diagnose even when suspected because of the low sensitivity of biliary brush cytology in this setting. Survival after the diagnosis of cholangiocarcinoma is poor and is often considered a contraindication to liver transplantation. Some centers have had favorable outcomes with liver transplantation preceded by radiation and chemotherapy.16
NATIONAL GUIDELINES
A recent review on the management of PSC has been formulated and contains current management guidelines.13 This review covers clinical aspects of PSC, diagnosis and management issues. The section on management includes recommendations for treatment of complications of chronic cholestasis and a review of the variety of immunosuppressive, anti-inflammatory, and antifibrotic agents tested to date with the acknowledgment that no therapy has yet to show an improvement in the natural history of the disease.
DRUG-INDUCED CHOLESTASIS
Drugs are a common cause of cholestasis. A spectrum of drug-induced liver injury ranges from acute reversible cholestasis to chronic cholestasis with loss of bile ducts. In a large study of 1100 cases, acute cholestasis accounted for about 17% of liver-related adverse drug reactions.17 Drugs can interfere with various aspects of bile acid metabolism including uptake, transport, and secretion at the hepatocyte level.18

Drug-induced cholestasis can be categorized into acute and chronic forms (Table 2).19 The acute forms are subdivided into cholestasis without inflammation ("bland" cholestasis), cholestasis with inflammation, and cholestasis with bile duct injury. Chronic forms include a vanishing bile duct syndrome and a sclerosing cholangitis-like syndrome.

Drug-induced cholestasis can be accompanied by nausea, anorexia, malaise, and pruritus.19 Symptoms can occur weeks to months after beginning treatment. Drugs that cause cholestasis with bile duct injury often are accompanied by additional clinical features such as fever, rigors, jaundice, and tender hepatomegaly mimicking acute cholangitis. Drugs that result in a vanishing bile duct syndrome may lead to progressive cholestasis with prolonged jaundice and pruritus, and occasionally cirrhosis and liver failure. The most important tool in the diagnosis of drug-induced cholestasis is a careful medical history eliciting from the patient a history of taking prescribed, over-the-counter, or alternative medications including herbs. Biliary obstruction should be excluded with an imaging study (ultrasound or computerized tomography [CT] scan) of the biliary tree. Principle treatment is withdrawal of the drug. Management of symptoms associated with cholestasis are similar to those for PBC.

Most cholestatic hepatic injury will resolve with withdrawal of the offending medication. A small subgroup of patients will develop progressive liver disease resulting in biliary cirrhosis and liver failure.
OTHER CONDITIONS ASSOCIATED WITH INTRAHEPATIC CHOLESTASIS
SEPSIS
Intrahepatic cholestasis is often seen in patients who have sepsis. It is hypothesized that conjugated hyperbilirubinemia occurs in sepsis because of impaired canalicular transport of conjugated bilirubin induced by lipopolysaccharide.20 The cholestasis of infection is often seen in severely ill hospitalized patients who are frequently in the intensive care unit (ICU). Other factors may contribute to the cholestasis including medications and total parenteral nutrition. Calculus or acalculous cholecystitis or biliary obstruction is often a concern in this setting. Ultrasound can be a very helpful diagnostic tool in this circumstance. Ultrasound is noninvasive and can be done in an ICU setting. Therapy for sepsis-induced cholestasis consists of treating the underlying infection. Outcomes usually are dictated more by the patient's underlying disease than the cholestasis itself.
MALIGNANCY
Primary liver cancer (hepatocellular carcinoma), and metastatic cancer all are associated with a liver enzyme pattern suggestive of cholestasis. They are more properly categorized as infiltrative disorders but are discussed here because of their similarity to cholestatic diseases. Hepatocellular carcinoma, once a relatively uncommon tumor, has been increasing in frequency over the last 2 decades because of its association with hepatitis C-induced cirrhosis. In this setting, the estimated incidence of the development of hepatocellular carcinoma is 1% to 4% per year.21 Cirrhosis from causes other than hepatitis C, particularly hepatitis B and hemochromatosis, are also associated with the development of hepatocellular carcinoma. Hepatocellular carcinoma is often suspected in patients with previously stable cirrhosis who experience a precipitous clinical decline without other explanation. The diagnosis is made by abdominal imaging techniques including ultrasound, CT scan, and MRI.

Therapeutic approaches to hepatocellular carcinoma include surgical resection, liver transplantation, and techniques designed to shrink the tumor, such as alcohol injection or radiofrequency ablation.

Metastatic carcinoma can also present with cholestasis. The hepatic component is usually found after the diagnosis of carcinoma is made, although it is occasionally the presenting feature. Cholestasis can also occur in patients as a paraneoplastic syndrome in the absence of metastatic disease to the liver. This non-metastatic cholestasis has been described in non-Hodgkin's lymphomas, prostate cancer and renal cell carcinoma.22-25

GRANULOMATOUS LIVER DISEASES
Granulomatous liver diseases are more accurately classified as infiltrative diseases but are discussed here because the pattern of liver enzyme abnormality resembles that seen with cholestasis. Granuloma formation in the liver occurs in a variety of disorders including systemic infections from bacteria, viruses, fungi, Rickettsia, spirochetes and parasites; drugs and chemicals; immune-mediated diseases such as sarcoidosis and primary biliary cirrhosis; and neoplasms such as Hodgkin's disease (Table 3).26,27 The list of commonly used drugs that result in hepatic granulomas is quite extensive and includes among others allopurinol, quinidine, sulfonamides and sulfonylureas. The finding of granulomas on liver biopsy is often expected, for example, in patients with suspected primary biliary cirrhosis who present with cholestasis and a positive mitochondrial antibody or patients with known sarcoidosis who present with cholestasis. On the other hand, when granulomas are found on liver biopsy unexpectedly or as part of an evaluation for a systemic illness, then a thorough investigation should be undertaken to look for the underlying cause.

Evaluation should begin with a careful history including, for example, risk factors for HIV, exposure to tuberculosis, or exposure to farm animals (a risk for brucellosis and Q fever). As exposure to drugs is a common cause of granulomatous liver disease, a history of medication use is essential. Further diagnostic testing is often necessary to ascertain the etiology and should include a chest x-ray; serological evaluation for fungi, HIV, Brucella, Treponema, viruses, mitochondrial antibody and angiotensin converting enzyme level; tuberculin skin testing, and special stains of the liver biopsy for fungus and AFB. More extensive evaluation such as abdominal or chest CT scanning may be necessary if lymphoma is suspected.

Treatment of granulomatous liver disease is disease specific. It may be as simple as stopping an offending drug. In a subgroup of patients, no etiology can be found.28 A trial of corticosteroids in these patients with idiopathic granulomatous hepatitis who are symptomatic with fever myalgias and arthralgias may be helpful. Consideration should be given to empiric antituberculous therapy prior to instituting corticosteroids.
INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Intrahepatic cholestasis of pregnancy (ICP) may occur in the second or third trimester. There appears to be a genetic component as it has been reported to occur in family members.29 It is likely that hyperestrogenemia associated with a pregnancy plays a role.30 Altered metabolism of progesterone has also been implicated. The hallmark clinical feature of intrahepatic cholestasis of pregnancy is pruritus. Jaundice may occur and laboratory data show the typical features of cholestasis including elevated serum bile acids, alkaline phosphatase and total bilirubin. Ursodeoxycholic acid has been used in ICP for relief of pruritus and it appears to be safe for mother and fetus.31 Symptoms resolve within several days of delivery but may recur during subsequent pregnancies.
HEPATITIS (VIRAL AND ALCOHOLIC)

Occasionally, viral hepatitis may present with signs and symptoms of cholestasis characterized by jaundice and pruritus. The clinical course can last for several months.32

Alcoholic hepatitis often presents with features of cholestasis. It is often accompanied by fever and the clinical presentation can be confused with cholangitis. A careful medical history is essential to confirm a history of ethanol abuse or dependency.
GENETIC DISORDERS
Rare syndromes result from mutations of genes responsible for transporting biliary constituents from the space of Disse across the basal lateral (sinusoidal) membrane and across the canalicular membrane into the bile duct. Transporter gene mutations can result in hereditary cholestasis and include such disorders as Byler's disease and benign recurrent intrahepatic cholestasis.33 Byler's disease is characterized by cholestasis occurring early in life progressing to cirrhosis and death, usually in early childhood. Benign recurrent intrahepatic cholestasis is characterized by episodic jaundice and pruritus lasting for several weeks to months with long symptom-free intervals. The disease does not progress to cirrhosis. Multiple family members can be affected. Cystic fibrosis can result in cholestasis due to gene mutations at the level of the bile duct resulting in inspissated bile.34
GRAFT-VERSUS-HOST-DISEASE
Graft-versus-host disease (GVHD) can be seen within the first 100 days after bone marrow transplantation (acute GVHD) or after that time (chronic GVHD). It occurs in up to 50% of patients after bone marrow transplant and is felt to be caused by T cells of the donor marrow reacting against host antigens resulting in cytokine damage of the affected organ. GVHD can affect the skin, liver and gastrointestinal tract. Although hepatic involvement is usually associated with cholestatic liver enzymes, other causes of cholestasis are common in this patient population and GVHD often has to be distinguished from viral infections, drug toxicity and hepatic veno-occlusive disease. Liver biopsy provides the most definitive way to distinguish the various causes of cholestasis in this patient population. Treatment of GVHD consists of prophylactic measures and treatment of active disease. The most common prophylactic regimen is a combination of methotrexate and cyclosporin or antithymocyte globulin. Various treatment regimens of acute of GVHD have been used including corticosteroids, antithymocyte globulin, tacrolimus and mycophenolate.35 Chronic GVHD has also been treated with a variety of agents including prednisone, cyclosporin, thalidomide, psoralen, ultraviolet irradiation, ursodeoxycholic acid, tacrolimus, rapamycin and mycophenolate.36 Less than half the patients treated for GVHD will sustain a cure. In general the more severe the skin liver or gut involvement the less favorable the outcome.
TOTAL PARENTERAL NUTRITION
Total parenteral nutrition (TPN) is associated with liver dysfunction resulting in steatosis, cholestasis, and cirrhosis. Intrahepatic cholestasis can occur after 2 to 3 weeks of TPN therapy and is associated with elevations in serum bilirubin and alkaline phosphatase.

Cholestasis usually reverses after TPN is stopped but is of concern if the patient requires long-term TPN. Progressive liver disease including cirrhosis may be associated with long-term TPN.37
POST LIVER TRANSPLANT CHOLESTASIS

Cholestasis is often seen after liver transplantation and is caused by a variety of conditions (Table 4).38 In the first few months after transplantation, cholestasis is often associated with bacterial infections or viral infections, particularly cytomegalovirus. Medications, both antibiotics and immunosuppressive drugs typically used after transplantation, are also associated with cholestasis. Acute cellular rejection is often heralded by the onset of cholestatic liver enzymes. Later in the course after transplantation, other etiologies of cholestasis are more common including chronic rejection, fibrosing cholestatic hepatitis resulting from recurrent hepatitis B or C or a recurrence of the original disease such as PBC or PSC.
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    39.

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