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Home , Abdominal pain, Jaundice

Clinical Case of the Month

A 44-Year-Old Woman With and Abdominal

Shane G. Guillory, MD; Matthew D. Jordan, DO; Bradley M. Spieler, MD; Matthew L. Safley, DO; John J. Hutchings, MD; Leslie A. Saketkoo, MD; Fred A. Lopez, MD, FACP

INTRODUCTION ties in her routine lab work, the patient was told to present to the for further workup. Primary biliary (PBC) is an autoimmune Vital signs at the time of presentation were only notable disease of the . It is characterized by a T-cell-mediated for a pulse of 100 beats per minute and a temperature of 99.0 attack of the small, intrahepatic ducts. The exact etiology degrees Fahrenheit. Head and neck examination revealed is unknown, but it is thought to be a result of a combina- sublingual icterus, as well as scleral icterus bilaterally. Ab- tion of genetic predisposition and environmental factors.1 dominal examination revealed mild tenderness to palpation The vast majority of patients affected by PBC are women.2 in the epigastric region, as well as the right upper quadrant The natural history of the disease varies by patient, but it is without rebound or guarding. A Murphy’s sign was absent. generally thought to be a chronic, progressive disease that The liver edge was palpated at 12 cm below the right costal carries a high mortality rate if not treated definitively with margin, and the was palpated at 3 cm below the left liver transplantation.3 The diagnosis of PBC is made with costal margin. Spider angiomata were noted in two spots the combination of clinical findings and laboratory data, on the right forearm, one spot on the left lower leg, and including antimitochondrial . The diagnosis can one spot on the back. Palmar erythema was noted as well. also be further confirmed with a . We present Initial laboratory workup revealed an elevated total a case of a woman who presented with , of 4.7 mg/dl (<1.3 mg/dl), alkaline phosphatase jaundice, and significant weight loss and was diagnosed of 795 U/L (20-120 U/L), GGT of 1,199 U/L (<55 U/L), with PBC based on autoantibody testing and liver biopsy. AST of 318 U/L (<46 U/L), and ALT of 289 U/L (<46 U/L). We also present a review of the epidemiology, etiology, Erythrocyte sedimentation rate was mildly increased at clinical findings, diagnosis, and treatment options for PBC. 22 mm/hr (0-20 mm/hr). Total cholesterol was 554 mg/ dl (<200 mg/dl), triglyceride level was 923 mg/dl (<150 CASE PRESENTATION mg/dl), and LDL level was 344 mg/dl (<130 mg/dl). An acute hepatitis panel was performed and was negative. An A 44-year-old woman with a past medical history of ammonia level was elevated at 72 Umol/L (9-35 Umol/L). cholelithiasis, status-post three years prior, drug screen and salicylate levels were not abnormal. presented to her primary care physician complaining of Imaging at the time of admission included a right up- progressively worsening right-sided abdominal pain of per quadrant ultrasound that revealed an enlarged liver at two months duration. She described the pain as “heavy,” approximately 25 cm in sagittal dimension with no focal located throughout the right side of her , 5/10 in hepatic abnormality, an enlarged spleen at approximately intensity, and progressively worsening throughout the day. 15.7 cm in sagittal dimension, normal flow in the portal She reported that the pain was exacerbated by lying on her vein, and an enlarged 2.3 cm node near the porta right side. She did admit to occasional radiation to her back hepatis. The was surgically absent. The com- and flank on the right side. The pain was not associated mon was noted to be normal, and no masses or with eating. She also denied any , , diar- free fluid were appreciated. Computed tomography of the rhea, , , , decreased appetite, abdomen on the day of admission confirmed the findings or pruritis. was otherwise positive for of the abdominal ultrasound (Figures 1, 2). A routine chest a 35-pound, unintentional weight loss over the prior three radiograph revealed no acute cardiopulmonary process. months. After her primary care physician noted abnormali- A rheumatologic workup was pursued. While anti-

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nuclear levels were nega- tive, the anti-mitochondrial antibody level was elevated at 26.5 units (<20 units). C-ANCA, P-ANCA, alpha- 1-antitrypsin level, transferrin, ceru- loplasmin, and AFP were all normal. An outpatient liver biopsy was performed to further confirm the sus- pected diagnosis of PBC. The results revealed severe portal lymphocytic and granulomatous inflammation with small interlobular duct ductope- nia/destruction and extensive peri- portal necroinflammatory changes, consistent with early-stage primary biliary cirrhosis (Figures 3, 4).

DISCUSSION

Primary biliary cirrhosis (PBC) is a progressive autoimmune disease that primarily affects women. Of the estimated 9,232 cases of PBC in the Figure 1: Axial contrast-enhanced CT demonstrates with an United States in 1996, 88.7% occurred 4 enlarged periportal lymph node (arrow), which measures greater than one centimeter in in females. Autoimmune-mediated maximal short axis diameter. destruction of intrahepatic bile ducts eventually leads to bile flow obstruc- tion, hepatic fibrosis, cirrhosis, and eventual liver failure. The exact etiology continues to be a subject of investigation, but it is described by Gershwin and Mackay to be a combination of genetic predisposi- tion and underlying environmental factors.5 Selmi et al. also suggest a genetic component by showing that the concordance of PBC in monozy- gotic twins is about 63%.1 Based on a systematic review of epidemiologic studies published by Boonstra et al. in the Journal of in 2012, worldwide incidence rates of PBC range from 0.33-5.8 per 100,000 and prevalence rates range from 1.91-40.2 per 100,000.6 Due to improved awareness and diagnosis earlier in the clinical course, 50-60% of patients are asymp- tomatic at the time of diagnosis.7 The most common symptoms seen in PBC are fatigue and pruritis.8 Pruritis is Figure 2: Coronal contrast-enhanced images show hepatosplenomegaly with the liver estimated to occur in 25%-75% of pa- and spleen measuring 28 and 23 centimeters in maximal craniocaudal dimensions, tients with PBC. It can often precede respectively. the actual diagnosis by several years, highlighting the need to consider PBC in any patient with pruritis that is not associated with a .8 The

130 J La State Med Soc VOL 166 May/June 2014 Figure 3: Image (left) shows a portal bile duct with lymphocytic infiltration of the epithelium and severe chronic inflammation in the surrounding tissue.

Figure 4: This image (below) reveals poorly formed granumlomas, with multiple epitheloid histocytes, within the portal triads and surrounding severe chronic inflammation.

pruritis in PBC is thought to be directly related to , As in this case, primary biliary cirrhosis will often decreased bile excretion, and subsequent accumulation of manifest with nonspecific findings on ultrasonography bile in the plasma and tissues. Fatigue is the most consistent and CT. Common imaging findings include signs of portal symptom of PBC, occurring in about 70%-80% of patients.8 hypertension, including , , and varices. The exact etiology is still unknown, but peripheral muscle is also often present, particularly in earlier fatigablilty9 and autonomic dysfunction10 as mechanisms phases of the disease. Enlarged upper abdominal lymph have been proposed. Less common symptoms may include nodes, which can enhance, are also a common finding.12 Sicca Syndrome (dry eyes and mouth), cutaneous calcinosis, MRI can have improved specificity, particularly in later Raynaud’s phenomenon, and dysphagia, as PBC can be as- stages of the disease, manifesting a periportal halo sign. sociated with other autoimmune diseases such as Sjogren’s This sign is characterized by low T1 and T2 signal intensity syndrome and scleroderma.2 The physical exam is often in a periportal distribution without mass effect. The sign normal in the asymptomatic patient. hyperpigmenta- reflects periportal parenchymal loss adjacent to regenera- tion due to melanin deposition may be seen earlier in the tive nodule formation. Aside from diagnostic utility, cross course, while jaundice is a late manifestation. Hepatomegaly sectional imaging can also be used for screening for hep- is found in about 70% of patients, and splenomegaly may tocellular carcinoma, as these patients a carry an increased develop as the disease progresses.2 risk (~5%).13,14 The diagnosis of PBC should always be considered in The classic findings on liver biopsy of patients with the setting of cholestasis after the exclusion of other liver PBC is asymmetric destruction of the bile ducts within the diseases. Most patients have a significantly elevated alkaline portal triads.2 Patients are further classified into stages (i.e., phosphatase with milder elevations in the aminotransferas- stage one through four) based on the degree of destruction es.11 The degree of elevations generally and the number of bile ducts involved. Stage 1 is inflamma- correlates with the severity of ductopenia and inflammation. tion localized to the portal triads, while stage 4 represents As the disease progresses, a rise in serum bilirubin, along end-stage .2 In 2009, The American Association with a decrease in serum and platelets, may signal for the Study of Liver Diseases (AASLD) published recom- the development of cirrhosis and portal hypertension. Se- mendations for the diagnosis of PBC.11 The diagnosis can rum cholesterol levels are often markedly elevated as well.11 be made if any two of the following three criteria are met: While anti-nuclear antibody (ANA) is only positive in ap- • Biochemical evidence of cholestasis based mainly proximately 70% of patients with PBC12, anti-mitochondrial on alkaline phosphatase elevation antibody (AMA) is found in nearly 95% of cases.11 • Presence of AMA

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• Histologic evidence of nonsuppurative destruc- suspected in any patient with unexplained cholestasis or tive cholangitis and destruction of interlobular pruritis. Timely diagnosis and early referral to a specialist bile ducts is imperative for these patients. The only FDA-approved therapy for PBC is ursode- oxycholic acid (UDCA).11 Several studies have supported REFERENCES the usefulness of UDCA in slowing the progression of liver failure and improving mortality rates.15 UDCA is indicated 1. Selmi C, Mayo M, Bach N, et.al. Primary Biliary Cirrhosis in for any patient with PBC and abnormal liver chemistries, Monozygotic and Dizygotic Twins: Genetics, Epigenetics, and regardless of stage. Appropriate dosing of UDCA is para- Environment. 2004; 127: 485-492. mount, as studies have shown superior results with a dose 2. Kaplan M and Gershwin M. Medical Progress: Primary Biliary Cirrhosis. N Engl J Med 1996; 353; 12: 1261-1273. of 13-15 mg/kg/day when compared to either a lower or 16 3. Boyer J, Shockcor W, and Mahl T. The Natural History of Primary higher dose. Some of the other that have been Biliary Cirrhosis. Trans Am Clin Climatol Assoc. 1992; 103: tested as a single agent in the treatment of PBC include 157–163. chlorambucil, penicillamine, cyclosporine, corticosteroids, 4. Jacobson D, Gange S, Rose N, et al. Epidemiology and Estimated azathioprine, mycophenolate mofetil, thalidomide, metho- Population Burden of Selected Autoimmune Diseases in the trexate, malotilate, and . None of the above-men- United States. Clinical Immunology and Immunopathology 1997; tioned medications have been shown to be of benefit, either Vol. 84, No. 3, 223-243. as single-agent treatments or in combination with UDCA.11 5. Gershwin, M and Mackay, I. The Cause of Primary Biliary Treatment of the major symptoms of PBC, including fatigue Cirrhosis: Convenient and Inconvenient Truths. Hepatology 2008; Vol. 47, No.2. and pruritis, is also often a focus of management. At this 6. Boonstra K, Beuers U, and Ponsioen C. Epidemiology of Primary time, there is no recommended therapy for fatigue in PBC. Sclerosing Cholangitis and Primary Biliary Cirrhosis: A Systematic The selective serotonin reuptake inhibitor, fluoxetine, has Review. Journal of Hepatology 2012; vol. 56, 1181-1188. not shown any improvement of fatigue in the setting of PBC, 7. Prince M, Chetwynd A, Craig W, et al. Asymptomatic Primary while modafinil, a used for excessive daytime Biliary Cirrhosis: Clinical Features, Prognosis, and Symptom sleepiness, has shown some benefit.11 Pruritis in PBC is not Progression in a Large Population Cohort. Gut 2004; 53: 1216. generally relieved by UDCA. The AASLD recommends 8. Bergasa N, Mehlman J, and Jones E. Pruritis and Fatigue in Primary that sequestrants be used as a first-line treatment Biliary Cirrhosis. Clinical Liver Disease. 2003. Vol.7, 879-900. 9. Goldblatt J, James O, and Jones D. Grip Strength and Subjective for pruritis, followed by , oral opiate antagonists, 11 Fatigue in Patients with Primary Biliary Cirrhosis. JAMA 2001; or sertraline for refractory cases. Outcomes for liver trans- 285 (17): 2196-7. plantation in patients with PBC are generally more favorable 10. Newton J, Davidson A, Kerr S, et al. Autonomic Dysfunction than transplants for other indications. Transplantation also in Primary Biliary Cirrhosis Correlates with Fatigue Severity. improves fatigue, pruritis, and bone disease in PBC.11 Timing European Journal of Gastroenterology and Hepatology. 2007; 19: of transplantation is key and can be better determined by 125-132. using one of several prognostic formulas. One of the most 11. Lindor K, Gershwin M, Poupon R, et al. Primary Biliary Cirrhosis: widely used, the Mayo model, takes into account several AASLD Practice Guidelines. Hepatology. July 2009: 291-304. factors, including serum bilirubin level, 12. Blachar A, Federle M, and Brancatelli G. Primary Biliary Cirrhosis: Clinical, Pathologic, and Helical CT Findings in 53 Patients. level, age, , and presence or absence of Radiology 2001; 220: 329-336. 17 peripheral . In combination with the Mayo model, 13. Wenzel J, Donohoe A, Ford K, et al. MR Imaging Findings and the Model for End-Stage Liver Disease (MELD) is also used Description of MR Imaging Periportal Halo Sign. American to guide timing of liver transplantation. Up to 20%-25% of Journal of Roentgenology. 2001; 176: 885-889. patients who undergo transplantation for PBC will have 14. Knowlton J, Taylor A, Reichelderfer M, et al. Imaging of recurrent disease in 10 years; however, cyclosporine-based Inflammation: An Update. American Journal of immunosuppression appears to reduce recurrence risk.18 Roentgenology. 2008; 190: 984-992. In conclusion, PBC is a progressive, autoimmune dis- 15. Lindor K, Therneau T, Jorgensen R, et al. Effects of on Survival in Patients with Primary Biliary Cirrhosis. ease of the liver seen primarily in women. It is diagnosed Gastroenterology. 1996; 110: 1515-1518. based on a combination of clinical findings and laboratory 16. Angulo P, Dickson E, Therneau T, et al. Comparison of Three data, with elevation of alkaline phosphatase and the pres- Doses of Ursodeoxycholic Acid in the Treatment of Primary Biliary ence of AMA being the hallmarks. The most consistent Cirrhosis: A Randomized Trial. Journal of Hepatology 1999; 30: symptoms of PBC are fatigue and pruritis. Skin hyper- 830-835. pigmentation due to melanin deposition may also be seen 17. Weisner R, Porayko M, Dickson R, et al. Selection and Timing of early in the course, while jaundice is a late presentation. Liver Transplantation in Primary Biliary Cirrhosis and Primary Per the AASLD practice guidelines, the diagnosis is largely Sclerosing Cholangitis. Hepatology. 1992; vol. 16: 1290-1299. based on biochemical evidence of cholestasis, presence of 18. Charatcharoenwitthaya P, Pimentel S, Talwalkar J, et al. Long- term Survival and Impact of Ursodeoxycholic Acid Treatment for AMA, and liver biopsy. The only FDA-approved medica- Recurrent Primary Biliary Cirrhosis After Liver Transplantation. tion for treatment of PBC is UDCA, which has been shown Liver Transplantation 2007; 13:1236-1245. to improve survival. Liver transplantation is a definitive treatment with overall favorable outcomes. PBC should be

132 J La State Med Soc VOL 166 May/June 2014 Dr. Guillory is a Chief Resident of the Internal Medicine Program in the Department of Medicine at Louisiana State University Health Sciences Center in New Orleans. Dr. Jordan is a second-year Resident in Internal Medicine in the Department of Medicine at LSUHSC-New Orleans. Dr. Spieler is an Assistant Professor in the Department of Radiology at LSUHSC-New Orleans. Dr. Safley is a Chief Resident of the Department of Pathology at LSUHSC-New Orleans. Dr. Hutchings is an Assistant Professor in the Department of Gastroenterology at LSUHSC-New Orleans. Dr. Saketkoo is an Assistant Professor in the Department of Rheumatology; Scleroderma and Patient Care and Research Center Director; and Associate Director of the Rheumatology Fellowship at LSUHSC-New Orleans. Dr. Lopez is the Richard Vial Professor and Vice Chair for Education in the Department of Medicine at LSUHSC-New Orleans.

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