Primary Biliary Cholangitis

Etiology

Primary biliary cholangitis (PBC) is an autoimmune disorder. Researchers theorize that patient with primary biliary cirrhosis has both genetic predisposition with the right environmental trigger. The prevalence of the disease is 100-fold higher in first degree relatives of the index patient, which strongly suggests a genetic predisposition. Various research has indicated associated environmental trigger in animal models, which includes urinary tract infection, reproductive hormone replacement, nail polish, cigarette smoking and xenobiotics, and toxic waste sites. The inflammation is thought to result from a direct insult of environmental factors and toxins.[4][5][6]

Epidemiology

The true incidence of primary biliary cholangitis  is rising as more screening tests such as liver chemistry and lipid profile are performed in otherwise healthy persons. Primary biliary cholangitis is common among women of middle age worldwide. The disease ratio among females to males is 9:1. The diagnosis is usually made in women aged between 30 and 60. Primary biliary cholangitis is mostly thought to be a disease of Europe and North America. However, incidence and prevalence are widely variable across different countries. The age-adjusted incidence of primary biliary cirrhosis in the United States per 1 million person-years for women is 45, and 7 for men, the prevalence per 1 million persons is 654 for women and 121 for men.[5][7][8]

Pathophysiology

The pathogenesis of primary biliary cholangitis is thought to be related to the interaction between genetic predisposition and environmental triggers. The genetic predisposition is suggested by a strong prevalence of the disease in first-degree relatives, with an odds ratio of 11. There is also a high degree of concordance in monozygotic twins. Daughters of index women have the highest relative risk for the development of primary biliary cholangitis. Several human leukocyte antigen (HLA) alleles associations have been reported with primary biliary cirrhosis, which includes DRB1, DR3, DPB1, DQA1, and DQB1. HLA-DRB1*08 is common in European and Asian descent, whereas HLA-DRB1*11 has been found to be protective.[8][9][10]

The environmental triggers include toxic waste, cigarette smoking, nail polish, hair dye, and various xenobiotics (e.g., Escherichia coli, Mycobacterium gordonae, Novosphingobium aromaticivorans). These environmental triggers induce the autoimmune reaction in genetically susceptible patients, which is evident by the presence of a humoral and cellular response to an intracytoplasmic antigen, the presence of anti-mitochondrial antibody (highly specific) and involvement of T lymphocytes in the destruction of bile ducts. In addition, bacteria containing lipoylated proteins lead to immune response targeting their own lipoylated proteins via molecular mimicry. When apoptosis occurs in somatic cells, the exposed epitope is blocked by the attachment of a glutathione residue.

Primary biliary cirrhosis is associated with highly specific autoantibodies. The anti-mitochondrial antibody is found in 85% of the cases. The anti-mitochondrial antibody binds to lipoic acid containing the E2 component of the pyruvate dehydrogenase complex that is located on the mitochondrial inner membrane. Other antibodies highly associated with primary biliary cirrhosis are antinuclear antibody (ANA), anti-multiple nuclear dot antibody (anti-MND), anticentromere antibody, and antinuclear envelop antibody. Especially, ANA and anti-MND are considered to be surrogate markers in AMA-negative primary biliary cirrhosis.

Histopathology

As mentioned in pathogenesis, the development of primary biliary cholangitis is the result of the interaction between genetic predisposition and an environmental trigger. Once the genetically susceptible patient is exposed to the aforementioned environmental toxins or bacteria, humoral ( B cell-mediated) and cellular (T-cell mediated) responses occur. B cells and T cells target antigens that infiltrate the liver and start attacking bile ductular cells leading to the destruction of small interlobular bile duct cells. The destruction of bile duct cells leads to the obstruction of bile drainage from canaliculi, which results in cholestasis and the destruction of hepatocytes. This cholestatic hepatitis subsequently leads to progressive fibrosis and cirrhosis.

History and Physical

Patients with primary biliary cholangitis can be asymptomatic or may present with jaundice, pruritus, and fatigue. Asymptomatic patients are incidentally diagnosed when they are found to have abnormal liver chemistry during evaluation for some other cause. Jaundice is secondary to cholestasis. Pruritus occurs in about 20% to 70% of patients, which is thought to be the neurocutaneous effect of retained bile salts. Another recent theory for pruritus is the association of elevated levels of lysophosphatidic acid, which is a product of circulating phospholipase and autotaxin, the levels of which are elevated in the case of cholestasis. Patients typically complain of worsening pruritus at night, in hot and humid weather, and when the skin is dry. Few patients may complain of vague right upper quadrant pain and mild cognitive impairment. Malabsorption and steatorrhea have also been reported in the case of primary biliary cholangitis, which is thought to be related to the deficiency of fat-soluble vitamins.

Patients with primary biliary cholangitis have various clinical findings on physical exam, which usually correlate with the stage of disease at presentation. About 40% of patients have skin complaints such as dry skin, hyperpigmentation, xanthelasma, xanthomas, jaundice, dermatographism, and fungal infection of the feet. Due to dry skin and pruritus, excoriations from scratching are common in primary biliary cholangitis patients. Hepatomegaly can be seen in both asymptomatic patients and at the later stage of the disease. Splenomegaly is common more at the later disease state. Stigmata of chronic liver disease such as spider nevi, ascites, edema, proximal, and temporal muscle wasting are more common as the liver disease progresses and patients are cirrhotic. Patients with primary biliary cholangitis can have other autoimmune conditions such as Hashimoto thyroiditis, CREST syndrome, Sjogren syndrome, rheumatoid arthritis, telangiectasias, and celiac disease. Osteoporosis, renal tubular acidosis, various skin conditions (lichen planus, discoid lupus, pemphigoid) are also commonly associated with primary biliary cirrhosis.

Evaluation

The diagnostic criteria for  primary biliary cholangitis include an absence of any other liver disease, no evidence of extrahepatic biliary obstruction on imaging, and at least 2 out of 3 of the following:

1. Elevation of alkaline phosphatase (ALP) at least 1.5 times upper limit of normal (ULN)
2. Presence of antimitochondrial antibody (AMA) with a titer of 1:40 or higher
3. Histopathological evidence of primary biliary cirrhosis (nonsuppurative destructive cholangitis or "florid duct lesion" and destruction of interlobular bile ducts with a predominance of lymphocytic infiltration).

Liver biopsy is not required for diagnosis but is helpful in disease prognosis and staging.[10][11]

Asymptomatic patients with abnormal liver chemistry, especially abnormal alkaline phosphatase, should be evaluated for primary biliary cirrhosis. Patients who present with vague right upper quadrant pain, unexplained pruritus, fatigue, jaundice, skin hyperpigmentation, and unexplained weight loss should also be evaluated for primary biliary cirrhosis.

Patients who are suspected of having primary biliary cirrhosis should undergo a right abdominal ultrasound, magnetic resonance cholangiopancreatogram (MRCP), or endoscopic retrograde cholangiopancreatogram (ERCP) to rule out the extrahepatic biliary obstruction. Once the extrahepatic obstruction is ruled out, AMA should be obtained. In some instances, IgM is elevated.

In cases of atypical disease presentation with elevated ALP but normal AMA, alternative diagnosis, and liver biopsy should be considered for diagnosis. However, with typical clinical features of primary biliary cholangitis and positive AMA, but normal ALP liver biopsy is not required.

Patients with primary biliary cholangitis also have a deranged lipid profile due to cholestasis. Fifty percent of patients have elevated cholesterol, which clinically manifests as xanthomas and xanthelasmas. Primary biliary cholangitis patients also have iron deficiency anemia due to chronic blood loss secondary to portal hypertensive gastropathy.Primary biliary cholangitis patients who have already developed cirrhosis may have coagulopathy (elevated prothrombin time), thrombocytopenia, and leukopenia in addition to anemia.

Treatment / Management

The goal of therapy in primary biliary cholangitis is to prevent the disease progression and manage the symptoms and complications related to chronic cholestasis.[11][12][13](A1)

Ursodeoxycholic acid (UDCA) is approved by the food and drug administration (FDA) for the treatment of PBC. It is a hydrophilic bile salt, which stabilizes hepatocyte membranes against toxic bile salts and inhibits apoptosis and fibrosis. The recommended dose is 13 mg/kg to 15 mg/kg per day. Patients benefit most when UDCA is started at an earlier stage, which has been shown to delay the progression of the disease and the development of cirrhosis. UDCA also leads to histological improvement.

In patients who do not respond to UDCA, obeticholic acid (OBCA) an alternative FDA-approved medication with restriction use can be administered with UDCA. OBCA is a farnesoid X receptor agonist, that helps to reduce ALP, GGT, and transaminase levels due to its antifibrotic and choleretic properties. However, it does not improve survival or disease-related symptoms.

Complications of chronic cholestasis

Bone disease: Osteoporosis and pathologic fracture is the most common bone disease in cholestatic liver disease such as primary biliary cholangitis. Hence, it is recommended that the Dexa scan be obtained at the diagnosis of primary biliary cirrhosis. This can be prevented by daily oral vitamin D and calcium supplementation and daily exercise. Estrogen therapy is recommended in a postmenopausal patient with primary biliary cholangitis has been shown to prevent loss of bone mass or bone mineral density.

Fat-soluble vitamin deficiency: Deficiency of fat-soluble vitamins A, D, E, and K are secondary to malabsorption due to decreased amounts of bile salts in the intestinal lumen. Levels of these vitamins should be checked periodically and supplemented accordingly.

Hyperlipidemia: About 85% of patients with primary biliary cholangitis have a deranged lipid profile. As the disease progress, HDL decreases, and LDL increases. Statins are recommended and have not shown to have a deleterious effect on liver function. In addition, patients with primary biliary cirrhosis and abnormal lipid profile have not shown to have elevated risk for myocardial infarction and strokes.

Pruritus: The actual cause of pruritus is understood poorly in primary biliary cholangitis Nonetheless, various agents have been shown to provide symptomatic relief. These are cholestyramine, rifampin UDCA, naltrexone, and antihistamines like diphenhydramine and hydroxyzine.

Steatorrhea: The cause for steatorrhea in primary biliary cholangitis is thought to be secondary to a decreased level of bile acid in the small intestine. Patients who have other coexisting autoimmune diseases such as celiac disease and scleroderma, small intestinal bacterial overgrowth (SIBO) can be the cause for steatorrhea as well. It is essential to find out the cause of steatorrhea and treat it accordingly. In patients who do not have sufficient bile acids in the small intestine, the medium-chain triglycerides (TGs) should be substituted for long-chain TGs in the diet, and total fat intake should be reduced. In the case of SIBO, intermittent broad-spectrum antibiotics can be used.

Liver transplant: Liver transplant is the standard gold treatment for primary biliary cholangitis. Patients with primary biliary cholangitis will develop complications related to cirrhosis (hepatic encephalopathy, recurrent ascites, severe portal hypertensive gastropathy, bleeding, or hemorrhage secondary to gastric or esophageal varices). They will also have disabling symptoms such as fatigue, intractable pruritus, and severely deranged bilirubin level in the absence of liver cancer. These patients should be evaluated for a liver transplant.

Differential Diagnosis

The differential diagnoses of primary biliary cholangitis are comprised of all the diseases which result in cholestasis, pruritis, and deranged liver profile. All middle-aged women presenting with pruritis and jaundice must be evaluated in the context of primary biliary cholangitis. Some of the more significant differentials are given below:

• Biliary obstruction/stricture
• Primary sclerosing cholangitis
• Hepatitis
• Drug-induced liver disease

Staging

The staging system devised by Scheuer is as follows:

• Stage 1: Portal stage associated with bile duct changes, and/or portal inflammation
• Stage 2: Periportal fibrosis and/or inflammation with dilated but intact portal tracts
• Stage 3: Septal stage: Septal fibrosis with active inflammation and/or paucicellular septa
• Stage 4: Cirrhotic: Variously sized nodules and varying degrees of inflammation

Prognosis

The most reliable indicators of a patient's prognosis suffering from primary biliary cholangitis are the rise in serum bilirubin level and the Mayo risk score. On the basis of bilirubin levels the prognosis can be determined as follows:

• Bilirubin constantly above 2 - mean survival is 4 years
• Bilirubin constantly above 6 - mean survival is 2 years
• Bilirubin constantly above 10 - mean survival is 1.4 years

In a study, it was determined that fatigue levels may also be a prognostic indicator of primary biliary cholangitis.[14]

Complications

The following complications may arise from primary biliary cholangitis:

• Osteoporosis
• Malabsorption
• Hyperlipidemia
• Esophageal motility dysfunction
• Renal tubular acidosis
• Liver cancer
• Autoimmune thrombocytopenia
• Hypoglycemia
• Myelopathy