ALP is coded by three separate genes and found in many locations in the body—liver, bone, placenta, kidneys, and intestine.¹ Its precise function is unknown. In the liver it appears to downregulate the secretory activities of the intrahepatic biliary epithelium.² Its half-life is 7 days, its site of degradation is unknown, and its clearance from serum is independent of the functional capacity of the liver or the patency of the bile ducts.³ The intestinal contribution (≈10% to 20%) is of limited clinical importance.⁴ Subjects older than 60 years have higher ALP values (up to 1.5 times normal) than younger adults, from the liver in older men and from bone in postmenopausal women.⁵

If there is an isolated increase in ALP, it is important to ascertain that this is of liver origin. For practical purposes in older adults, we mainly need to establish whether the raised ALP level is of liver or bone origin. The most practical approach is to measure the γ-glutamyl transpeptidase (GGT) level, whose elevation may also reflect biliary disease. However, GGT is an inducible enzyme that is not completely specific for hepatobiliary disease. It is elevated in people who drink large quantities of alcohol⁶ or take medicines such as phenytoin.⁷

ALP isoenzyme levels can be requested with the caveat that the test is heat-labile; bone and liver isoenzymes differ only slightly in electrophoretic mobility, sometimes leading to inconclusive results. 5′-Nucleotidase is a more specific biliary enzyme than GGT but is not measured routinely.⁸ Refer to the investigative pathway for raised ALP levels shown in Figure 75-1.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is now the investigation of choice for characterization and staging of hepatic, pancreatic and splenic lesions and for imaging the biliary tree using MRCP. It does not involve the use of radiation. MRCP is commonly used for the diagnosis of gallstones, assessment of common bile ducts, intrahepatic ducts, or pancreatic ducts for stenotic lesions or stones, and investigating pancreatitis or abdominal pain of uncertain cause.

A strong magnetic field is used to align rotating hydrogen protons within the tissue being imaged, and T1 and T2 relaxation times are used to create the final image. In T2-weighted images, water appears white and the liver dark, which makes the biliary tree easy to visualize, hence making MRCP the investigation of choice for biliary pathology.

Older patients can find MRI difficult to tolerate because they have to lie supine and still for at least 30 minutes. Noise levels can be high because of vibration of the magnetic coils, and ear plugs or headphones need to be worn. Claustrophobia due to the tight cylindrical scanner can lead to a significant number of patients being unable to complete the test. Sedation can be used to improve compliance. Open coil magnets are increasingly being used for claustrophobic patients and for patients who are too large for the cylindric scanner.

MRI contrast agents (e.g., gadolinium) are safer than the iodinated contrast agents used for CT scanning and rarely cause contrast reactions. However, they can cause contrast nephropathy and, in rare cases, nephrogenic systemic fibrosis in patients with moderate to severe chronic kidney disease.

Contraindications include implanted devices such as cardiac pacemakers, implantable cardioverter-defibrillators (ICDs), nerve stimulators, cochlear implants, and embedded metallic foreign bodies such as intraorbital metallic fragments that may have been present from the working days of the now-retired patients. Transdermal patches need to be removed prior to MRI. There is a risk of contrast nephropathy with gadolinium-based contrast agents in those with advanced chronic kidney disease.

The following are not contraindications and are considered safe for MRI: joint prostheses, coronary or peripheral vascular stents, prosthetic heart valves, sternal wires, inferior vena cava filters, and embolization coils. The composition of intracranial aneurysmal clips needs to be ascertained because most may not be safe during MRI.

Genetics of Primary Biliary Cirrhosis

Genome-wide association studies (GWAS) and iCHIP studies of PBC have been undertaken in those of European or Japanese ancestry and have shown that the human leukocyte antigen (HLA) complex makes an important contribution to the genetic basis of PBC. Risk haplotypes associated with PBC include those carrying DRB1*08 and DRB1*04 alleles. Protective haplotypes include those carrying DRB1*11 and DRB1*15 alleles. A total of 27 non-HLA risk loci for PBC have also been identified, harboring highly plausible candidate genes that are mainly involved in innate or acquired immune processes.²⁰

Clinical Features

Although most PBC patients are asymptomatic at the time of diagnosis, two characteristic symptoms of the disease, fatigue and pruritus (itch), can occur at any point in the disease course. Although the prevalence of fatigue (up to 78% of patients) and pruritus (20% to 70%) are similar,²¹ pruritus is a more specific symptom of PBC than fatigue. Both fatigue and pruritus are complex symptoms, and their cause in PBC remains incompletely understood. Also, for reasons that are currently unknown, neither fatigue nor pruritus correlates with the severity, histologic stage, or duration of PBC. Fatigue is often constant over time but pruritus may diminish in severity, especially during late stages of diseases. A recent study has observed that the intensity of itch depends on the age at disease presentation. In this study, younger patients (<30 years) scored 64% higher in pruritus score than those who presented after 70 years of age.²² Nocturnal pruritus will affect sleep, worsen fatigue, cause mood changes and cognitive impairment, and impair the overall quality of life. Other features of PBC include dry eyes and/or dry mouth (sicca syndrome), xanthelasma, xanthomata, portal hypertension, osteoporosis, and hyperlipidemia.

Management

UDCA is the only drug licensed by the U.S. Food and Drug Administration (FDA) for the treatment of PBC. UDCA is a bile acid that acts as a choleretic agent, with fewer hepatotoxic properties than endogenous bile acids.¹⁹ In a number of prospective randomized controlled trials, its use at more than 10 mg/kg of body weight (BW)/day has been shown to improve liver biochemistry significantly, slow histologic progression (in those with early stage disease), reduce the risk of developing varices, and improve liver transplant–free survival of patients.²³ However, it has not been shown to be effective in reducing pruritus or improve fatigue. Current guidelines recommend the use of UDCA for patients with PBC who have positive tests for AMAs and elevated liver biochemical markers. The optimal dose of UDCA is 13 to 15 mg/kg BW/day, and it is be used for patients at any stage of PBC, as long as the liver biochemistry is abnormal.²¹ UDCA is generally well tolerated, with occasional side effects of diarrhea, abdominal discomfort, nausea, and vomiting. The benefit of UDCA for patients with positive AMA tests and normal liver biochemistry is less clear; therefore, these patients should not be considered for UDCA treatment.

Clinical Features

Patients may be asymptomatic and diagnosed accidentally on routine blood tests. Asymptomatic PSC is found in 20% to 40% of patients investigated for abnormal LFTs. Occasionally, the symptoms have a relapsing and remitting course. Typical symptoms on presentation are jaundice, right upper quadrant pain, pruritus, and fatigue. One third of patients have episodes of acute cholangitis, with recurrent attacks.

Investigations

Liver enzyme levels, and especially ALP levels, are raised in most patients; perinuclear antineutrophil cytoplasmic antibodies (pANCAs) may be detected in 26% to 85% of PSC cases, but they lack specificity for diagnosis. Overlap syndromes with other forms of liver disease have been described. PSC with autoimmune hepatitis-like features has been referred to as autoimmune cholangitis. These patients usually present with high serum ALT levels, modest or no elevations in serum alkaline phosphatase levels, high titers of ANAs and anti–smooth muscle antibodies (SMAs), and histologic liver findings typical of autoimmune hepatitis.

Characteristic stricturing of biliary tracts is seen on MRCP. Dominant strictures develop during the disease course in about 36% to 63% of patients.³² This leads to further elevation of liver enzyme levels, usually ALP. Dominant strictures develop de novo or are due to diffuse inflammatory periductal fibrosis; more recently, Candida has been hypothesized as the causative infective organism.^33,34 These are treated with endoscopic retrograde cholangiopancreatography (ERCP) and biliary stent insertions; however, the development of a dominant stricture is associated with poor outcome.³⁵ Liver biopsy is rarely required to diagnose PSC. It shows periductal inflammation in the early stages, which then extends to periportal areas, leading to septal fibrosis and necrosis, eventually resulting in frank cirrhosis of the liver.³⁶