Diagnosis and management of patients with primary biliary cirrhosis

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Primary biliary cirrhosis (PBC) is now most frequently diagnosed as a result of an assessment following the identification of abnormal liver biochemistry in an otherwise well patient. An increasing number of patients are diagnosed after investigations of unexplained fatigue. Cholestatic pruritus can be a presenting feature in some, and occasional patients will present with end‐stage liver disease. Improvements in the range and effectiveness of therapies over the next few years are likely to increase the importance of an early diagnosis for optimal therapy.

Role of Anti‐Mitochondrial Antibodies (AMAs)

Although AMAs appear not to contribute directly to the pathogenesis of PBC, they remain an important diagnostic marker but not a prognostic marker (titers and specificity do not affect the risk of disease progression). AMAs at a titer > 1:40 in the context of cholestatic liver biochemistry are more than 95% sensitive and specific for the diagnosis.1 AMAs in the context of normal liver function tests (LFTs) indicate an increased risk of disease development in the future, but current advice is to not treat these patients until an abnormality in the liver biochemistry is seen.2 Anti‐nuclear antibodies (ANAs) unique to PBC are also seen in up to 25% of patients (with some geographical variation).3 Reacting with nuclear pore and rim structures, they produce distinctive immunofluorescence patterns that must be distinguished from the homogeneous staining pattern seen in autoimmune hepatitis (AIH). PBC‐specific ANAs, in contrast to AMAs, do appear to have prognostic significance and are associated with more aggressive disease.4 Both immunofluorescence (Fig. 1) and enzyme‐linked immunosorbent assay‐based approaches are available for both AMAs and ANAs in PBC (which technique is used is largely an operational decision).

Figure 1.

Immunofluorescence patterns in ANAs. Representative AMA and ANA indirect immunofluorescence staining patterns are shown: AMA staining in (A) a rat liver, (B) the Hep2 cell line, (C) rat gastric parietal cells, and (D) a rat kidney; ANA staining in (E) homogeneous nuclear and (F) nuclear rimlike patterns in the Hep2 cell line; and peripheral staining in (G) the Hep2 cell line and (H) rat liver cells.

When, If Ever, Is Biopsy Needed?

Because of the diagnostic value of AMAs (and PBC‐specific ANAs) in the context of cholestatic liver biochemistry, liver biopsy is no longer routine for the diagnosis of PBC.5 Biopsy does, however, provide important prognostic information and is likely to play an increasing role in the identification of disease variants for which specific therapies may increasingly become available. Biopsy plays a key role in the diagnosis of AMA‐negative (and ANA‐negative) disease and in the identification of disease with features of AIH, which may be amenable to corticosteroid therapy (Fig. 2). The principal use of biopsy in the future is likely to lie in stratifying patients who are unresponsive to first‐line therapy with ursodeoxycholic acid (UDCA) for second‐line therapy.

Figure 2.

Biopsy images: PBC versus predominant AIH. (A) Destructive cholangitis (arrow) and mild mixed portal inflammatory infiltrate with focal interface activity (arrowheads) in PBC (hematoxylin and eosin, ×10). The inset shows characteristic granulomatous cholangitis and a dense lymphoplasmacytic infiltrate involving another portal tract (hematoxylin and eosin, ×20). (B) Autoimmune cholangiopathy with features suggestive of overlap with AIH. This indicates that steroid use may be appropriately considered: moderate, predominantly plasmacytic, chronic inflammation in the portal tract and focal lymphocytic cholangitis (white arrows) with mild degenerative changes in the interlobular bile duct epithelium; moderate interface activity (white arrowheads) including plasma cells; and zone 1 spotty necrosis (black arrow; hematoxylin and eosin, ×20). The inset shows evidence of chronic cholestasis with dark brown intracytoplasmic granules of copper‐associated protein in periportal hepatocytes (black arrowheads; orcein, ×40).

AMA‐Negative PBC

Approximately 3% to 5% of PBC patients are AMA‐ and ANA‐negative, even when they are assessed with sensitive assays such as immunoblotting. In this group, disease is often more advanced at diagnosis (because of the delay in diagnosis), but it is otherwise clinically similar to antibody‐positive disease. The presence of elevated immunoglobulin M (IgM) levels (also seen in AMA‐positive patients) can be a pointer to the diagnosis. Liver biopsy is essential for making the diagnosis (Fig. 3).

Figure 3.

Flowchart providing simple guidance for the diagnosis of PBC.

Treatment of Fatigue and Itch

Fatigue and pruritus are the characteristic symptoms of PBC, can occur at any stage in the disease process, and do not typically respond to primary therapy with UDCA. They are related only in the sense that disturbed sleep secondary to pruritus can contribute to fatigue. Because pruritus can represent a result of biliary obstruction due to the increased risk of gallstone disease in patients with PBC, bile duct obstructions should be excluded in patients with new‐onset pruritus. The first‐line therapy uses bile sequestrants, although tolerability can be an issue. Rifampicin is a useful second‐line agent and probably acts through its pregnane X receptor agonist function.6 Tolerability can again be an issue. Oral opiate antagonists are used in a number of countries as third‐line therapy.7 All other therapies, including physical approaches such as nasobiliary drainage and albumin dialysis, are experimental.8, 9 Trials of novel agents are currently ongoing, and it is likely that new and improved agents will emerge in the near future. Transplantation is highly effective but difficult to justify in patients with low Model for End‐Stage Liver Disease scores.

Fatigue is a major problem for patients and is difficult to treat. The first step is to exclude predisposing processes, including pruritus and AIH overlap, and concurrent fatigue‐causing conditions such as hypothyroidism, which are seen at an increased frequency in patients with PBC. Autonomic dysfunction,10 sleep disturbance (other than that secondary to pruritus), and depression are all associated with fatigue in patients with PBC and can be addressed as part of an integrated approach to fatigue reduction (Table 1 and Fig. 4). Fatigue in patients with PBC does not appear to improve with transplantation.11

Table 1.

Prevalence of Other Immune‐Mediated Diseases in Patients With PBC

Disease	Prevalence (%)	References
Sjogren's syndrome	3.5‐47	12, 13, 14, 15, 16
Raynaud's syndrome	12‐24	12, 13
Autoimmune thyroid disease	9‐23	12, 13, 17, 18
Scleroderma	8‐17	12, 16, 19
Rheumatoid arthritis	1.8‐17	12, 13, 16
Type 1 diabetes mellitus	<1	12
Celiac disease	3	20, 21
Systemic lupus erythematosus	1.8‐3	13, 16

Figure 4.

Factors contributing to fatigue in PBC.

Timing of Transplantation

Outcomes following liver transplantation are good for patients with PBC, although disease recurrence is an emerging problem.22, 23 The timing of transplantation can be complicated by the fact that liver synthetic function is often well maintained until the very end stage, when it can deteriorate rapidly; a patient can change from being “too well” for transplantation to “too sick” in a short period of time. The potential for rapid deterioration should be considered when one is embarking on discussing transplantation for PBC patients. It is the authors' practice to mention transplantation when the bilirubin level exceeds 3 mg/dL and to formally discuss it at 6 mg/dL.24

Abbreviations

AIH

autoimmune hepatitis

AMA

anti‐mitochondrial antibody

ANA

anti‐nuclear antibody

IgM

immunoglobulin M

LFT

liver function test

PBC

primary biliary cirrhosis

UDCA

ursodeoxycholic acid.