Primary Biliary Cirrhosis

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Diagnosis and reasoning

The icteric patient is one of the more concerning presentations in primary care; a focused clinical evaluation and investigative workup are key towards quickly and accurately diagnosing these individuals. Considering the lady in this case, note the presence of associated pruritus; while the pathophysiology of this phenomenon is still unclear, it is generally accepted as being more suggestive of cholestasis (which might be due to hepatic or extrahepatic causes). She also experienced the same symptoms around an year ago, indicating that this might be an episodic etiology. An astute clinician might wonder if this might be due to gallstones. Her physical examination does not reveal any significant abnormalities, except for mild hepatomegaly with right hypochondriac tenderness, and clinical findings secondary to the pruritus; these are non-specific. Thus, the next step should be targeted investigations, starting with a liver profile, and ultrasound scan of the abdomen. The liver profile reveals the presence of direct hyperbilirubinemia, confirming the presence of cholestasis; note also the presence of marked elevation of both alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) - this is suggestive of involvement of the biliary tract. The ultrasound scan is normal, essentially excluding gallstones; however, the biliary tract should be properly imaged via magnetic resonance cholangiopancreatography (MRCP). This too does not show a structural abnormality or obstruction of the hepatobiliary tract. Another possibility comes to mind, which would fit all of the above findings - primary biliary cirrhosis (PBC); note also that her age and gender are compatible with the disease. Thus, it is justifiable to order an autoimmune assay. This turns out to be positive for antimitochondrial antibodies (AMA), which are 95% specific for PBC; in the presence of biochemical evidence of cholestasis, this satisfies the diagnostic criteria for PBC outlined by the American Association for the Study of Liver Disease (AASLD). Note that viral hepatitis should be definitively ruled out in these patients (particularly since the treatment of PBC may involve immunosuppressants). However, she tests negative in this regard. Ursodeoxycholic acid (UDCA) is essential to delay progression of the disease. Corticosteroid therapy will improve the biochemical and histological findings. It should be appreciated that UDCA is not particularly effective in treating the pruritus encountered in these patients; cholestyramine may be helpful in this regard. Liver transplantation is a treatment of final resort, and is not indicated right now.


Discussion

Primary Biliary Cirrhosis (PBC) is a chronic liver disease characterized by progressive destruction of bile ducts. While earlier considered rare, the prevalence of PBC has dramatically increased over the years; it is currently estimated at approximately 35 per 100,000 population, with an incidence of 5 per 100,000 persons per year; the disease accounts for up to 2% of deaths due to cirrhosis. It is unknown if this is because the incidence is actually increasing, or if it is a result of improved and early detection. PBC demonstrates a marked female preponderance, with a male to female ratio of upto 10:1. The median age at diagnosis typically ranges between 55 and 65 years, although, occasionally a patient might present in his/her fourth decade. A very high prevalence of PBC (as much as 1 in 750 individuals) is noted in European and North American women over 55 years of age, who are presumably the group at highest risk. Existing evidence indicates that PBC is an autoimmune disorder; however, the exact mechanism of liver injury is yet to be determined. The serological hallmark of the disease is the presence of Antimitochondrial Antibodies (AMA), with a very high specificity of >95%. These antibodies target members of a family of enzymes which catalyze the oxidative decarboxylation of keto acid substrates. The epithelial cells lining the small and medium sized bile ducts have an abundance of these enzymes, hence the predilection for destruction of small and medium sized bile ducts in PBC. In general, regeneration of destroyed bile ducts is ineffective; the resulting intrahepatic cholestasis leads to retention of toxic substances, giving rise to further damage; the vicious cycle thus continues, ultimately resulting in cirrhosis. The underlying etiology is postulated to be a combination of genetic predisposition and environmental triggers. In this respect, there is a clear association of PBC with certain HLA types. Urinary tract infections, hormone replacement therapy, cigarette smoke and xenobiotics have been identified as potential environmental triggers. Note also that certain autoimmune diseases such as autoimmune thyroiditis, CREST syndrome, celiac disease and keratoconjunctivitis sicca have a slightly increased incidence in these patients. In most cases, PBC has an indolent course which may extend over decades; the rate of progression, however varies greatly between individuals. In the early stages of the disease, the majority of patients are asymptomatic. With progression of the disease, symptoms do appear, with the first and most common symptom being chronic fatigue. Other common features include, pruritus, xerophthalmia and xerostomia; the last two are an integral part of Sicca syndrome which coexists in over 50% of cases of PBC. Note that pruritus can be severe, potentially significantly impacting the patient's quality of life. Some patients may also complain of right hypochondriac pain. Physical examination is usually normal but may occasionally reveal hepatomegaly, xanthelasma, xanthoma, and features suggestive of portal hypertension such as splenomegaly and spider naevi. Jaundice is found in only 10% of cases; it is generally considered to be indicative of advanced disease. Malabsorption of fat soluble vitamins, an increased risk of osteoporosis and certain malignancies (particularly, hepatocellular carcinoma and breast carcinoma) have also been reported in association with advanced PBC. PBC should be diagnosed in the presence of chronic cholestasis where other causes of liver disease are excluded. To establish the diagnosis, the American Association for the Study of Liver Disease (AASLD) recommends at least two of the three following criteria to be met: - Biochemical evidence of cholestasis based mainly on elevation of alkaline phosphatase. - Presence of AMA. - Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. While the aforementioned histological appearance is characteristic of the disease, this requires a liver biopsy; when considering the very high specificity of AMA, this is no longer considered mandatory. It is prudent to reserve liver biopsy for AMA negative patients and for exclusion of comorbidities such as non-alcoholic steatohepatitis and autoimmune hepatitis - particularly when the diagnosis is doubtful. Other notable biochemical and serological abnormalities seen in PBC include, hyperlipidemia, hypercholesterolemia with an increased HDL fraction, elevated immunoglobulin (particularly IgM) levels, increased erythrocyte sedimentation rate (ESR), thrombocytopenia and positive Antinuclear Antibodies (ANA); the latter is identified in at least 20% to 50% of cases. Imaging studies such as abdominal ultrasonography, CT imaging and MRI may reveal nonspecific findings such as hyperechogenicity of the liver and features of portal hypertension. The only therapy for PBC approved by the U.S. Food and Drug Administration (FDA) is ursodeoxycholic acid (UDCA); the drug has been proven to slow down disease progression and to reduce the need for liver transplantation. Alternative drugs include corticosteroids, as well as immunosuppressants such as methotrexate, colchicine and cyclosporin. Both of these classes of drugs reportedly improve the biochemical and histologic findings. Interestingly, while UDCA is used to treat the pruritus encountered in patients with intrahepatic cholestasis of pregnancy (ICP), it is much less effective in individuals with PBC. Mild to moderate pruritus can be successfully treated with antihistamines, although extreme caution is essential when using these drugs in patients with hepatic encephalopathy. 5-hydroxytryptamine receptor type 3 (5HT-3) antagonists, cholestyramine, propofol, and rifampicin have shown promise in experimental approaches to treat pruritus; plasmapheresis and albumin dialysis are used in cases refractory to pharmacotherapy. Very recently obeticholic acid (OCA) came into light as a promising treatment for PBC, however the clinical trials in this regard are still ongoing. Note that patients with jaundice are predisposed to malabsorption of fat soluble vitamins (particularly vitamin K). If their INR is elevated, intravenous (IV) vitamin K should be administered for correction. Calcium and vitamin D supplementation is usually recommended to prevent osteoporosis; alternatively, hormone replacement therapy can be used to improve vertebral bone density in patients with PBC, as demonstrated by another clinical trial. Complications related to cirrhosis should be managed accordingly. Liver transplantation is the ultimate refuge, and is indicated in patients suffering from decompensated cirrhosis with treatment-resistant ascites, recurrent spontaneous bacterial peritonitis, encephalopathy, recurrent variceal bleeding, or hepatocellular carcinoma. Very rarely, liver transplantation is indicated for treatment resistant pruritus or severe osteoporosis even in absence of decompensated cirrhosis. Currently available clinical data does not emphasize that avoidance of any particular type of food would be beneficial, however maintenance of an ideal body weight is highly desirable in patients with superimposed steatohepatitis. Following liver transplantation, survival rates of up to 90% have been reported; however in approximately 20% to 25% of patients, the disease recurs within the first 10 years following transplantation.


Take home messages

  1. Primary Biliary Cirrhosis (PBC) is not as rare as once thought; it accounts for 2% of all deaths due to cirrhosis, and is a leading cause for liver transplantation.
  2. While most patients are asymptomatic in early disease, they gradually become symptomatic over time; chronic fatigue is the most common symptom.
  3. Antimitochondrial Antibodies (AMA) are more than 95% specific for PBC; thus, liver biopsy is generally not required in AMA positive patients.
  4. Ursodeoxycholic Acid (UDCA) is of proven benefit in delaying disease progression and reducing the need for liver transplantation.

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