Primary biliary cirrhosis (PBC) is now known as primary biliary cholangitis. It is an autoimmune disorder which leads to gradual destruction of intrahepatic bile ducts resulting into periportal inflammation, cholestasis. Prolonged hepatic cholestasis subsequently leads to cirrhosis and portal hypertension. Primary biliary cirrhosis is the most common cholestatic disease of middle-aged women in the United States.
Primary biliary cirrhosis 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 be due to a direct insult of environmental factors and toxins.
The true incidence of primary biliary cirrhosis is rising as more screening tests such as liver chemistry, and lipid profile is performed in otherwise healthy persons. Primary biliary cirrhosis is common among women of middle age worldwide. The disease ratio among female to male is 9:1. The diagnosis is usually made in women of age between 30 and 60. Primary biliary cirrhosis is mostly thought to be a disease of European and North American disease. However, the incidence and prevalence is 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.
The pathogenesis of primary biliary cirrhosis is thought to be related to the interaction between genetic predisposition and environmental triggers. The genetic predisposition is suggested by a strong prevalence of disease in first degree relatives, with the 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 development of primary biliary cirrhosis. 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 was found to be protective.
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 but 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 that contain lipoylated proteins leads to immune response targeting own lipoylated proteins via molecular mimicry. When apoptosis occurs in somatic cells, the exposed epitope is blocked by attachment of a glutathione residue.
Primary biliary cirrhosis is associated with highly specific autoantibody. The anti-mitochondrial antibody is found in 85% of the cases. The anti-mitochondrial antibody binds to lipoic-acid containing E2 component of the pyruvate dehydrogenase complex that is located on the mitochondrial inner membrane. Other antibodies highly associated with primary biliary cirrhosis is an 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.
As mentioned in pathogenesis, development of primary biliary cirrhosis is the result of interaction between genetic predisposition and an environmental trigger. Once the genetically susceptible patient is exposed to aforementioned environmental toxins or bacteria, humoral ( B cell-mediated) and cellular (T-cell mediated) response occur. B cells and T cells target antigens that infiltrate liver and start attacking bile ductular cells leading to the destruction of small interlobular bile duct cells. Due to the destruction of bile duct cells, leads to obstruction bile drainage of canaliculi which results in cholestasis and destruction of hepatocytes. This cholestatic hepatitis subsequently leads to progressive fibrosis and cirrhosis.
Patients with primary biliary cirrhosis can be asymptomatic or present with jaundice, pruritus, and fatigue. Asymptomatic patients are diagnosed when the abnormal liver chemistry is discovered done for other reasons. 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. Other 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 case of cholestasis. Patients typically complain worse pruritus at night, in hot and humid weather and dry skin. Few patients may complain of vague right upper quadrant pain, mild cognitive impairment. Malabsorption and steatorrhea have also been reported in case of primary biliary cirrhosis which is thought to be related to deficiency fat-soluble vitamins.
Patients with primary biliary cirrhosis have various clinical findings on physical exam, which usually correlates 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 feet. Due to dry skin and pruritus, excoriations from scratching are common in primary biliary cirrhosis patients. Hepatomegaly can be seen in both asymptomatic patients and at the later stage of a 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 is more common as the liver disease progresses and patients are cirrhotic. Patients with primary biliary cirrhosis can have other autoimmune conditions such as Hashimoto thyroiditis, CREST syndrome, Sjogren syndrome, Rheumatoid arthritis, telangiectasias, celiac disease. Osteoporosis, renal tubular acidosis, various skin conditions (Lichen planus, discoid lupus, pemphigoid) are also common in primary biliary cirrhosis patients.
The diagnostic criteria for Primary biliary cirrhosis 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:
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 to have 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 cirrhosis and positive AMA but normal ALP liver biopsy is not required.
Patients with Primary biliary cirrhosis also have deranged lipid profile due to cholestasis. Fifty percent of patients have elevated cholesterol, which clinically manifests at xanthomas, xanthelasmas. Primary biliary cirrhosis patients also have iron deficiency anemia due to chronic blood loss secondary to portal hypertensive gastropathy. Primary biliary cirrhosis patients who have already developed cirrhosis may have coagulopathy (elevated prothrombin time), thrombocytopenia, and leukopenia in addition to anemia.
The only medicine approved by Food and Drug Administration for treatment of primary biliary cirrhosis is ursodeoxycholic acid (UDCA). It is a hydrophilic bile salt, which stabilizes hepatocyte membranes against toxic bile salts and inhibits apoptosis and fibrosis. Typical dose administered is 13 mg/kg to 15 mg/kg daily. Patients benefit most when UDCA is administered at an earlier stage, which has been shown to delay the progression of disease and development of cirrhosis. UDCA also leads to histological improvement.
Patients who do not respond to UDCA, an obeticholic acid (OBCA) can be added with UDCA. OBCA is a farnesoid X receptor agonist, which helps to reduce ALP, GGT, transaminases level due to its antifibrotic and choleretic properties. 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 cirrhosis. Hence, it is recommended that 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 in a postmenopausal patient with primary biliary cirrhosis has 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 is 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 cirrhosis have 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 has\ not shown to have elevated risk for myocardial infarction and strokes.
Pruritus: The actual cause of pruritus is understood poorly in primary biliary cirrhosis. Nonetheless, various agents have 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 cirrhosis is thought to be secondary to a decreased level of bile acid in the small intestine. Patients who have other co-existing autoimmune diseases such as celiac disease and scleroderma small intestinal bacterial overgrowth (SIBO) can be the cause for steatorrhea as well. It is very important to find out the cause for steatorrhea and treat accordingly. In patients who do not have sufficient bile acids in the small intestine, substitution of medium-chain triglycerides (TGs) for long-chain TGs in the diet and decrease total fat intake. In case of SIBO, intermittent broad-spectrum antibiotics can be used.
Liver transplant: Liver transplant is the standard gold treatment for Primary biliary cirrhosis. Patients with primary biliary cirrhosis will develop complications related to cirrhosis (hepatic encephalopathy, recurrent ascites, severe portal hypertensive gastropathy, bleeding or hemorrhage secondary to gastric or esophageal varices). They also will have disabling symptoms such as fatigue, intractable pruritus, and severe bilirubin level in the absence of liver cancer. These patients should be evaluated for liver transplant.
The staging system devised by Scheuer is as follows:
Primary biliary cirrhosis can recur after a liver transplant. The rate of recurrence has been reported in transplant centers from 0% to 35%. Recurrence of primary biliary cirrhosis typically has been found to be anywhere from 3 to 6 years after transplant. Tacrolimus-based immunosuppression is thought to be the strongest risk factor for recurrence of Primary biliary cirrhosis. The AMA may persist after transplant; this cannot be accounted for from recurrence of the disease. The diagnosis of primary biliary cirrhosis recurrence post-transplant is made histologically.
The management of PBC is best done in a multidisciplinary fashion. The disorder has no cure and carries a high morbidity and mortality. The aim of treatment is to slow down the disease progression and improve the quality of life. Besides the physicians, the nurse, mental health counselor, pharmacist, and physical therapist play a critical role in the management of these patients. The nurse should educate the patient on the management of itching and use of moisturizers. The dietitian should educate the patient on a healthy diet to prevent osteoporosis and deficiency of fat-soluble vitamins. The pharmacist should educate the patient on the Sicca syndrome and how to avoid dry eyes and mouth. Because of extreme fatigue, the patient should enroll in a physical therapy program or some type of physical activity. Finally, the patient should see a mental health counselor as the disorder can result in premature death. The patient should be urged to join a support group and closely follow up with the healthcare provider. (Level V)
In patients with a low serum albumin, the survival can range from 3-6 years. However, if the bilirubin levels are consistently high, the survival is significantly reduced with an average survival of 1.7 years. Almost all patients with PBC develop moderate-to-severe fatigue, which persists even after a liver transplant. Universally, once patients develop symptoms, the outcome is grim. (Level V)
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