Transplantation for Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology characterized by lymphocytic cholangitis and segmental destruction of intralobular bile ducts within the liver. Patients with PBC may progress gradually to cirrhosis, liver failure, and ultimately death or liver transplantation (LT). Survival free of liver transplantation can be prolonged by ursodeoxycholic acid (UDCA) in the majority of patients receiving therapy. However, in patients not responding to UDCA therapy the need for LT is more likely. Furthermore, LT not only prolongs survival in patients with PBC but also helps improve health-related quality of life. Although disease recurrence in the transplanted liver may occur, the data showing a significant clinical burden from recurrent PBC are lacking to date.

Epidemiology and Etiology

PBC is not limited to a certain geographical distribution or a specific race. European studies have estimated the incidence rate of PBC at 0.33 to 5.8 cases per 100,000 person-years with prevalence rates varying from 0.5 to 39 cases per 100,000 person-years. Conversely, population-based studies on the epidemiology of PBC remain scarce worldwide. In Olmsted County, Minnesota, the overall incidence (adjusted for age and gender) of PBC between 1975 and 1995 was 2.7 cases per 100,000 person-years, whereas in women the incidence was 4.5 per 100,000 person-years as compared to 0.7 per 100,000 person-years in men. Similar data have emerged from European studies as well. These data suggest that an estimated 3500 new cases of PBC may exist within the United States each year. In addition, a recent systematic review suggests that prevalence rates of PBC are increasing with time.

Case-control epidemiological studies have also identified several risk factors associated with PBC, including cigarette smoking, family history of PBC, tonsillectomy, prior urinary tract infections, and a previous history of obstetric cholestasis.

Current evidence suggests that PBC develops from an immune-mediated pathogenetic process. This hypothesis is supported by the presence of serum antimitochondrial antibodies (AMAs) in patients with PBC. The E2 subunit of the pyruvate dehydrogenase complex is targeted by AMAs in most patients with PBC. However, it remains unclear how detectable immunological abnormalities are responsible for the histological changes that occur with PBC.

Cross-reactivity between self and microbial antigens, also referred to as molecular mimicry , has also been proposed as a pathogenetic mechanism for PBC. The association between PBC and recurrent urinary tract infections is supportive of this hypothesis. T-cell clones from PBC patients can be activated by Escherichia coli peptides that are analogous to the pyruvate dehydrogenase complex E2 subunit. Helicobacter pylori and Chlamydia may also make a similar contribution to disease pathogenesis. This concept remains a theory that requires further study and confirmation.

Several environmental triggers may also be involved in the pathogenesis of PBC. This is further supported by many epidemiological studies showing clustering of the disease on genetic and geographical basis. In New York, PBC cases were found to occur increasingly around toxic waste disposal sites. In England the majority of PBC cases in Sheffield shared a water reservoir, whereas an increase in PBC cases was attributed to former coal mining activities within the region adjacent to Newcastle. Hence it is plausible to consider that environmental factors, whether infectious, toxic, or chemical, may play a role in disease pathogenesis.

Recent work has also further elucidated the genetic predisposition for developing PBC. Screening asymptomatic family members of PBC patients using serum AMA has demonstrated a 2% to 4% rate of seropositivity, with daughters of PBC patients having 60 times the risk for developing PBC as compared to unrelated controls. Furthermore, the concordance rate of PBC in identical twins is among the highest reported for any autoimmune disease. Initial studies, including candidate and genome-wide association studies, among patients with PBC and controls have identified a number of single nucleotide polymorphisms that could have functional associations with molecular pathways associated with PBC development.

Clinical Features

Diagnosis

The diagnosis of PBC requires meeting at least two of the following three criteria: (1) a cholestatic serum liver biochemistry profile for a minimum of 6 months, (2) serum AMA positivity, and (3) liver histological examination results consistent or compatible with features associated with PBC. The majority of patients typically meet the first two criteria, and liver biopsy when performed demonstrates nonsuppurative inflammation of the bile ducts.

Elevation of serum alkaline phosphatase level is the biochemical hallmark of PBC. Serum alanine aminotransferase and aspartate aminotransferase levels are usually elevated as well, but at levels that are less than five times the upper limit of normal. Conversely, serum bilirubin levels are normal at diagnosis but often rise once cirrhosis develops.

Serum AMA positivity occurs in 90% to 95% of patients with PBC. In the absence of a cholestatic liver biochemistry profile, serum AMA positivity can also be seen in patients with autoimmune hepatitis and less commonly in primary sclerosing cholangitis. The presence of clinical features without AMA positivity is referred to as AMA-negative PBC . Limited data suggest that the natural history and treatment response for AMA-negative PBC is similar to classic PBC. Other serum autoantibodies in patients with PBC include antinuclear antibodies, anti–smooth muscle antibodies, and anticentromere antibodies.

Typical features of PBC on liver histological examination include lymphocytic cholangitis, portal tract edema, and in rare cases ductopenia. The presence of granulomatous cholangitis (also termed the florid duct lesion ) is pathognomonic for stage 1 PBC. Although liver biopsy is not required for diagnosis in most patients, it does provide information on disease stage. The Batts-Ludwig staging system is most commonly used for PBC. Recent advances, including elastography imaging, can also provide information on disease stage and prognosis in PBC.

Presymptomatic Disease

Isolated elevations of serum alkaline phosphatase level in the absence of symptoms are the most common presentation in patients with PBC. Recent studies with prolonged follow-up of PBC patients have shown that when symptoms develop in patients with asymptomatic disease, the course of the disease becomes similar to patients who are symptomatic at baseline. This contradicts findings of earlier studies that showed improved outcomes in asymptomatic patients. The results of early studies may be attributed to lead-time bias, in which the diagnosis was made relatively early in asymptomatic patients as compared to patients with symptoms. This is also reasonable because of the natural history of the disease, whereby presymptomatic patients usually develop symptoms after 2 to 4 years of follow-up.

Symptomatic Disease

The relative frequency of symptoms and signs at presentation is given in Table 13-1 . Fatigue is the most common symptom reported, and its frequency may be as high as 70%. Alterations in central neurotransmitters and release of corticotropin hormone are hypothesized to play a role in the development of fatigue in PBC patients. Sleep disturbances resulting from itching or other causes, including depression, may also influence fatigue.

TABLE 13-1

Presenting Signs and Symptoms in Primary Biliary Cirrhosis

Feature	Prevalence (%)
No symptoms	40
Fatigue	70
Pruritus	30-50
Hepatomegaly	25
Hyperpigmentation	25
Splenomegaly	15
Jaundice	10
Xanthelasma	10

Pruritus occurs in 30% to 50% of subjects and is most often a presenting symptom before diagnosis. Pruritus in PBC has several proposed mechanisms, including endogenous opioids and serum bile acid levels. The severity of pruritus often increases at nighttime and is unrelated to histological stage of the disease. Notably, it appears that the pruritus severity resolves as the disease progresses.

Late-stage disease characterized by jaundice is uncommon at initial presentation. As the disease advances, complications related to portal hypertension such as variceal bleeding, ascites, and hepatic encephalopathy may occur.

Extrahepatic Autoimmune Diseases

Autoimmune diseases occurring outside the liver are common in 70% of patients with PBC. Keratoconjunctivitis sicca may occur in 75% of patients and constitutes dry eyes and xerostomia from secondary Sjögren’s syndrome. Other disorders include arthritis in 10% to 40%, thyroid disease (mainly Hashimoto’s thyroiditis) in 15% to 20%, and scleroderma or CREST (calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome in 10% of patients.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here