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UPMC Liver and Pancreas Institute (LPI) Molecular Mechanisms of Fatty Liver Disease by David A

UPMC Liver and Pancreas Institute (LPI) Molecular Mechanisms of Fatty Liver Disease by David A

Fall 2007 Pitt Digest

Inside This Issue

Page Two UPMC and Institute (LPI) Molecular Mechanisms of Fatty by David A. Geller, MD The UPMC Liver Center (LCC) was launched five years ago as a division of the Page 3 he UPMC Liver and Pancreas Institute Starzl Transplant Institute, and evaluates over Pancreaticobiliary (LPI) was established in 2006 to coordi- 500 new liver cancer patients per year. The Cancer Diagnosis T nate efforts among the clinical physicians and physicians and staff at the LCC specialize in

Pages Four and Five scientists managing patients with liver and the management of HCC, , GI Grand Rounds pancreatic diseases. Flagship LPI programs cancer, neuroendocrine cancer, include the Liver Cancer Center (LCC) and the and metastatic to the liver. Page Seven Center (PCC). The LCC Treatment options for liver cancer include Expanded Services and PCC function as multidisciplinary health surgical resection, , care teams at the forefront of providing regional , Yttrium-90 internal clinical services, innovative radiation, radiofrequency treatment strategies, and (RFA), systemic cutting-edge research for PATIENT REFERRALS chemotherapy and novel patients with liver and For Liver Cancer: gene therapy approaches. Page Eight pancreatic cancer. 412-692-2001 LCC surgeons, pioneers in What Is This? The LPI, directed by livercancercenter.upmc.com laparoscopic liver resection Dr. Adam Slivka (see for cancer, have

CENTERS OF EXCELLENCE: related article on page 3 of For Pancreatic Cancer: performed more than 200 this issue) and Dr. David of these minimally invasive • PANCREAS &BILIARY DISEASES 888-623-PANC (7262) Geller, has the following hepatic resections. • INFLAMMATORY BOWEL DISEASE pancreaticcancercenter.upmc.com specific goals: The UPMC Pancreatic • LIVER DISEASES Cancer Center (PCC) was • NEUROGASTROENTEROLOGY AND ✔ Establishment of an organizational structure MOTILITY DISEASES established in 2006 and is co-directed by implementing efficient delivery of healthcare • INTESTINAL HEALTH & Drs. Herbert Zeh and James Moser. The PCC services for patients with liver and pancre- NUTRITION SUPPORT provides state-of-the-art treatment for patients atic cancer within the UPMC Health System; • GASTROINTESTINAL CANCER with pancreatic cancer, pancreatic , and PREVENTION & TREATMENT chronic pancreatitis. The PCC evaluates more ✔ Coordination and cross-fertilization of the • WOMEN’S DIGESTIVE HEALTH than 300 patients with pancreatic cancer or established liver and pancreas centers of pancreatic lesions each year. excellence at UPMC Presbyterian, Monte- Pitt Digest fiore, Shadyside, and Passavant hospitals; is a publication of the ✔ A system-wide increase in overall clinic visits, Dr. Geller is Director of the UPMC University of Pittsburgh admissions, operative procedures, regional Liver & Pancreas Institute and is Division of , therapies and transplant referrals; and the Co-Director of the Liver Cancer Hepatology and Nutrition Center. He is the Richard L. ✔ Promotion of clinical and basic research Simmons Professor of Surgery Editors: activities for liver and pancreatic diseases. at the University of Pittsburgh. Toby O. Graham, MD Janet R. Harrison, MD Brian Ng, MD Joy Jenko Merusi, MA Division Highlights Understanding the Molecular Mechanisms of ittsburgh, in the minds of many physicians, is by Jaideep Behari, MD, PhD P synonymous with liver transplantation. The pioneering efforts of Thomas Starzl MD, recent recipient of the presti- gious National Medial of Science, made organ transplantation onalcoholic fatty liver disease, characterized by the a modern-day miracle. New developments in the care of N accumulation of fat in the liver in the absence of patients with liver disease are featured in this Pitt Digest. significant intake, is an increasingly common reason Dr. David Geller’s cover page feature on the new multi- for referral to hepatology clinics. NASH (for nonalcoholic disciplinary UPMC Liver Pancreas Institute (LPI) is comple- ) is a progressive form of fatty liver disease mented by articles by Drs. Adam Slivka and Kapil Chopra, that can lead to and liver cancer. Molecular who share leadership roles in the LPI. signaling pathways in the liver cell play an important role UPMC liver and pancreas teams have been highly effec- in the development of this disease. tive in providing innovative patient care and in advancing medical and surgical knowledge. Recently, LPI’s multidisci- plinary pancreas team authored the June, 2007 issue of Gastroenterology Clinics of North America, entitled Advances in the Diagnosis and Treatment of Pancreatic Diseases. Thirty-three faculty and advanced fellows from the University of Pittsburgh contributed to this state-of-the-art update, covering both malignant and non-malignant diseases. In this Digest, Dr. Jaideep Behari focuses on complex liver disease research, highlighting the clinical problems of fatty Compared with normal mice (panel A), knockout mice lacking β-catenin liver diseases. Having completed our group’s NIDDK T-32 protein in the liver (panel B) show increased steatohepatitis when exposed to a steatogenic diet. training program under the mentorship of Dr. Satdarshan Paul Monga, Dr. Behari joined our faculty in June, 2006 and Research in my laboratory is focused on understanding is a promising physician scientist in our Division. the role of one such molecular signaling pathway, called the Two of our clinical fellows, Drs. Carmen Meier and Wnt/β-catenin pathway, in the development of fatty liver Scott Cooper (who also contributed to the production of disease. We use genetically engineered mice lacking the another GI Rounds Online physician education program on β-catenin protein in the liver (called “knockout” mice) and chronic pancreatitis http://girounds.pitt.edu), provide the teaching cases in this issue. Our annual live physician experimentally induce hepatic steatosis to study alterations education program, What’s New in GI and Hepatology will in molecular processes within liver cells. Recently, we feature the Management of Female-Predominant GI Diseases found that our knockout mice, when exposed to a steato- and will be held on November 15 and 16, 2007. genic diet, have a striking increase in hepatic steatosis, in We look forward to future opportunities to address your some cases approaching 100 percent. Knockout mice also questions about UPMC’s digestive disease programs, patient have disturbances in several important metabolic pathways collaborations and research breakthroughs. Join us for Pitt in the liver and show more hepatic . We are currently GI’s educational offerings –- either in person or online! dissecting the molecular interactions that underlie these results, and future research plans include developing In good health, strategies which utilize these observations to design therapeutic interventions for this disease.

Dr. Behari is an assistant professor of medicine with the University of David C. Whitcomb, MD, PhD Pittsburgh Division of Gastroenterology, Giant Eagle Foundation Professor Hepatology and Nutrition. He practices of Cancer Genetics in the Division’s Center for Liver Diseases. Professor of Medicine, Cell Biology & Physiology and Human Genetics Chief, Division of Gastroenterology, Hepatology and Nutrition

2 R ESEARCH U PDATE

The State of Pancreaticobiliary Cancer Diagnosis by Adam Slivka, MD, PhD 19-9 (CA 19-9) and (CEA) may be elevated. Diagnostic imaging studies include CT scans and ith the unique dedication and expertise existing endoscopic ultrasound (EUS). CT scans using helical recon- W among faculty members of the Division of struction and IV contrast equipment can detect tumors up Gastroenterology, Hepatology and Nutrition and to 1cm in size, provide information about spread UPMC’s Oncologic Surgery and Transplant to distant organs, most commonly the liver Surgery groups, along with the creation and regional lymph nodes, and confirm of the Liver and Pancreas Institute invasion of blood vessels making the (LPI), UPMC is making major tumor inoperable. EUS can detect even advances to improve the early smaller tumors and has the added diagnosis and care of patients advantage of allowing safe fine needle afflicted with diseases of the aspiration with high diagnostic accuracy. pancreas and biliary system. The Although more than 90 percent of article which follows highlights our pancreatic are , current knowledge and practice in the there is an increasing recognition of early diagnosis and management of two precancerous conditions in both solid and potentially devastating diseases, cancer of the cystic pancreas tumors. Pioneering work at UPMC and pancreas and cholangiocarcinoma. other institutes has examined the role of molecular derangements in early diagnosis in susceptible individuals Pancreas Cancer and the recognition of precancerous lesions. DNA from individual cells can be examined for oncogenic . Of the 32,180 people in the United States diagnosed The only treatment offering a potential pancreatic cancer with pancreatic cancer every year, 31,800 will die from their cure is surgical resection with the operative approach disease. Pancreas cancer is the most lethal of all cancers depending on the location of the tumor. Although the and is the fourth highest cancer killer in the United States vast majority of patients will succumb to their disease, among both men and women. Early diagnosis of pancreas 20 percent of early-stage cancers may be cured with a cancer is problematic, since there are no specific symp- surgical resection. In other patients undergoing surgery for toms, and work-up for other conditions results in delayed curative intent but in whom the cancer recurs, survival is diagnosis. Typical symptoms are midline significantly improved compared to those who undergo radiating to the back associated with . Cancers medical treatment alone with chemotherapy and radiation. in the head of the pancreas cause obstruction which is usually painless. New onset of in an older Cholangiocarcinoma adult, new onset depression and upper may also Cholangiocarcinoma, a cancer of the biliary tree, is rare herald the development of pancreas cancer. and affects 2,000 to 3,000 patients each year in the Recent studies investigating pancreatic cancer (PC) risk United States. Common symptoms are obstructive , factors have determined that older age, male gender, itching, abdominal pain and weight loss. Blood tests show African ethnicity, , and chronic pancreatitis elevated liver injury, and tumor markers, CEA and CA19-9, may be linked to its development. A subgroup of PC has may be variably elevated. genetic components, and familial clustering may be seen. In the United States, the most commonly associated risk Diets, exposure to chemicals and pesticides as well as factor for cholangiocarcinoma is primary sclerosing cholan- gingivitis and periodontal disease have been linked to gitis (PSC), an inflammatory disease involving the bile pancreas cancers. ducts. The risk of developing cholangiocarcinoma in PSC While there are no specific blood tests for PC diagnosis, elevated liver injury tests may indicate malignant obstruction continued on page 6 of the bile duct, and tumor markers carbohydrate antigen

3 GRAND ROUNDS

A Rare Complication of Pregnancy

vitamin. She was married with (3995 grams) with two healthy children and denied use severe microvesicular and macro- by Carmen B. Meier, MD of any tobacco, alcohol or illicit vesicular steatosis. Gastroenterology Fellow drugs. Her family history was AFLP occurs in one out of 7,000 to not remarkable. 13,000 deliveries, most frequently Laboratory studies were significant during the third trimester and in for the following: total bilirubin Case Presentation 24 mg/dL, direct bilirubin 20 mg/dL, ALT 75 U/L, AST 127 33-year-old woman, 36 weeks U/L, ALP 324 U/L, INR 3 and A into her third pregnancy, pre- WBC 20,000/mm3 with a left sented with ten days of jaundice. shift. An abdominal ultra- She noticed dark urine and profound sound with Doppler evalua- fatigue during the past week, and her tion was essentially normal. husband reported that she fell asleep Acute fatty liver disease during conversations over the past of pregnancy (AFLP) was two days. During the few hours prior suspected. Fortunately, as to presentation, she had increasing the patient’s contractions uterine contractions. On physician became more frequent, her exam, she was jaundiced and drowsy membranes ruptured, and Figure 2: Liver demonstrating microvesicular steatosis but was easily aroused with verbal she delivered a healthy baby stimulation. She had asterixis. Her boy. Following delivery, her abdominal exam was significant mental status deteriorated multiparous women. Presenting further. She was intubated, symptoms are often nonspecific, such and transferred to an ICU as nausea, and abdominal shortly thereafter. pain. Elevated aminotransferases, A CT scan of the abdomen hyperbilirubinemia, leukocytosis, revealed a markedly enlarged thrombocytopenia and coagulopathy liver with extensive hepatic are often present. Patients can steatosis (Figure 1). A liver worsen rapidly with hypoglycemia, biopsy was performed on day pancreatitis and hepatic encephalopa- two of her hospitalization, thy. Imaging, such as ultrasound or showing severe microvesicu- MRI, is often performed but is rarely lar steatosis (Figure 2), con- helpful with diagnosis. The diagnostic firming the diagnosis of AFLP. gold standard is which The woman eventually suf- shows microvesicular hepatic steatosis. Figure 1: CT scan demonstrating hepatomegaly and fered seizures, and increased Severe HELLP syndrome as well as hepatic steatosis intracranial pressure was viral should be considered confirmed by jugular bulb in the differential diagnosis. for mild bilateral upper quadrant catheter placement. She was listed The pathogenesis of AFLP remains tenderness and a gravid abdomen. for liver transplantation and received a unclear. Current evidence implicates The patient’s preceding pregnancy cadaveric transplant seven days after disorders of lipid metabolism in the occurred three years ago. She initial presentation to the hospital. fetus with defects of mitochondrial became jaundiced during this Her mental status improved rapidly fatty acid oxidation, specifically long- previous pregnancy, but this resolved after transplantation, and she made chain 3-hydroxyl-CoA dehydrogenase spontaneously after delivery. Her a full recovery. The pathology of the continued on page 8 only medication was a prenatal native explanted liver showed massive

4 GRAND ROUNDS

Weight Loss and a Sunless Tan

head CT scans and a normal TSH. Addison in 1849 and has a preva- Stool studies for cultures, c. diff. tox- lence of 39 to 60 per million people. by Scott T. Cooper, MD ins, ova and parasites and fecal leuko- The mean age of diagnosis is 40 Gastroenterology Fellow cytes were normal. years. Seventy to 90 One week prior to percent of chronic pri- presentation, her mary adrenal insuffi- symptoms wors- Air ciency cases are due to Case Presentation ened, and the Fluid autoimmune adrenali- patient had a right tis. The remainder of 26-year-old woman with a past upper quadrant cases are caused by A medical history significant for ultrasound showing infections (e.g., tuber- depression and hypothyroidism possible biliary culosis, systemic fungal presented to the emergency room sludge without evi- infections or AIDS), 24 hours after a laparoscopic chole- Figure 1: CT scan of abdomen dence of biliary showing moderate perihepatic fluid and or heredi- cystectomy complaining of severe obstruction or pneumoperitonium. tary causes. The com- persistent nausea and vomiting. A CT cholecystitis. Due mon presenting signs scan (figure 1) showed the presence to these findings on the ultrasound and symptoms may be found in the of water density fluid in the perihep- the patient underwent an uneventful lower left table. Hyperpigmentation is atic and right pericolic space. The elective cholecystectomy without any the most common physical finding and pancreaticobiliary service was con- known complications. is usually more prominent in areas sulted to evaluate for a bile leak. The patient’s physical examination exposed to light and chronic friction. Four months prior to the cholecys- was remarkable for hypotension with The hyperpigmentation is due to tectomy, the patient experienced blood pressure of 94/54 pulse 88 increased melanin in the skin due to progressively severe and frequent and mild diffuse abdominal tender- elevated levels of adrenocorticotropic episodes of nausea and vomiting ness to deep palpation without signs hormone (ACTH). associated with a 45-pound weight of peritonitis. Laboratory evaluation An AM cortisol reading of less loss. No exacerbating or relieving was remarkable than three micrograms per deciliter factors were found for serum sodium is diagnostic of adrenal insufficiency. for the nausea. Common Presenting Signs of 133, potassium A value great than 19 micrograms The patient report- and Symptoms of Primary of 5.2, hemoglo- excludes the diagnosis. Intermediate ed intermittent Chronic Adrenal Insufficiency bin of 11.9 with a values require further testing, such watery diarrhea, normal MCV. CT as a cosyntropin stimulation test. anorexia, postural > Tiredness, weakness, depression scan findings were Further testing with a serum ACTH lightheadedness, > Anorexia, weight loss, thought to be con- level greater than 100 picograms per abdominal pain progressive gener- sistent with a nor- milliliter is diagnostic of primary > Dizziness, orthostatic hypotension alized weakness > Nausea, vomiting, constipation mal postoperative adrenal insufficiency. and fatigue. She or diarrhea state due to the Treatment replaces insufficient denied abdominal > Hyponatremia, hyperkalemia, lack of peritoneal steroids with 15mg hydrocortisone in pain, , chills, hypoglycemia, hypercalcemia, signs. Further the morning and 10mg in the after- melena or hema- mild normocytic , workup included noon along with 50 to 200 micro- tochezia. Her lymphocytosis, eosinophilia > Hyperpigmentation an AM cortisol grams of oral fludrocortisone as a complexion dark- > Autoimmune thyroid disease level, which was replacement for aldosterone. ened with little undetectable, and The patient was started on hydro- exposure to the a plasma corti- cortisone and fludrocortisone. Her sun. Three months prior to her chole- cotropin level of 143 picograms per nausea and vomiting resolved sig- cystectectomy, she had an extensive milliliter, which was consistent with nificantly within 24 hours, when she workup showing the following findings: chronic primary adrenal insufficiency could consume a normal diet. Within two normal upper endoscopies with or Addison’s disease. one month, her energy returned to normal small bowel , a normal Chronic primary adrenal insuffici- normal levels, she began regaining colonoscopy, normal abdominal and ency was first described by Thomas weight and her diarrhea resolved.

5 The State of Pancreaticobiliary Cancer Diagnosis continued from page 3

is approximately 15 percent. Approximately 80 percent of Like pancreatic cancer, surgery is the only curative PSC patients have inflammatory bowel disease, more often modality. Small tumors in the periphery of the liver may be ulcerative colitis than Crohn’s disease. Patients with cured in up to 40 percent of cases through resection of the chronic viral hepatitis and immune cholestatic liver involved segment of the liver. For tumors involving the disease are at increased risk for main bile duct outside of the liver, cholangiocarcinoma as are those with cure rates of up to 40 percent may rare congenital abnormalities of the be expected with early disease and Pancreas cancer is the biliary tree called . early diagnosis. The incidence of cholangiocarcinoma Unfortunately, the majority of appears to be increasing in North most lethal of all cancers patients with cancers of the pancreas America, Europe, Asia and Australia. and bile duct present too late to be Reasons for these increases are and is the fourth highest offered a curative operation. In these unclear but may be related to improve- instances, palliative surgery may ments in diagnostic modalities. cancer killer in the United improve survival and prevent suffering. Bile duct cancers may be located ERCP can be used to place temporary peripherally in the small bile ducts States among both men or permanent stents to relieve bile inside the liver or may be more centrally duct and digestive tract obstructions. located in the main biliary tree as it and women. Endoscopic ultrasound can be used leaves the liver and descends through to provide nerve blocks for patients the head of the pancreas into the duo- with unrelenting pain. Certain denum. Bile duct cancers are adenocarcinomas by pancreas tumors and premalignant lesions located in the histology. They are slow growing tumors, and the cells body and tail of the pancreas may be amenable to laparo- surround themselves with fibrous tissue making their diag- scopic resection, with surgeons at UPMC having the world’s nosis difficult. These tumors may be diagnosed by CT scan. largest published experience in laparoscopic resection for Using Endoscopic Retrograde Cholangio-Pancreatography pancreas tail tumors. (ERCP), catheters can be advanced into the bile duct with dye injected to visualize characteristic bile duct cancer blockages. Tissue may be obtained by brushing or biopsy. Dr. Slivka is a Professor of Medicine and is the Most recently, the therapeutic endoscopy team of our Associate Chief for Clinical Care with the Division of Division has been chosen to test a new miniature scope Gastroenterology, Hepatology and Nutrition. He is that can be passed through the standard ERCP scope also Co-Director for UPMC’s Liver Pancreas Institute. directly into the bile duct. Physicians at UPMC have used this new device, called the Spyglass, to improve diagnostic

yield in patients with cholangiocarcinoma.

References upon request. upon References

provided by Brian Ng, MD, Gastroenterology Fellow. Gastroenterology MD, Ng, Brian by provided This? Is What

ctions. inje B12 monthly included discharge on medications His g/dL. 10.4 to rose hemoglobin his discharge of day on and stay, hospital

. He was transfused four units of blood during his during blood of units four transfused was He . AMAG and anemia pernicious with diagnosed was and antibodies cell parietal gastric

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associated with an increased risk of gastric and tumor. carcinoid and adenocarcinoma gastric of risk increased an with associated

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), the most common subtype in the United States, is an autosomal dominant disorder characterized by an immune mediated immune an by characterized disorder dominant autosomal an is States, United the in subtype common most the ), AMAG ( gastritis

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What Is This Is What photo on page eight: eight: page on photo to Answer

6 Expanded Hepatology Services Complications of cirrhosis of the liver, including management of portal hypertension, and with the Liver Pancreas Institute hepatic encephalopathy; by Kapil B. Chopra, MD, FACP Screening and surveillance for and cholangiocarcinoma; and he Comprehensive Liver Program at the Liver Pan- T creas Institute (LPI) is responsible for the medical Evaluation and selection of patients who may be management of patients with . While appropriate liver transplantation candidates. based at the Center for Liver Diseases at the UPMC Presby- terian Hospital, liver clinical services are also offered at the LPI’s Comprehensive Liver Program facilitates an UPMC Passavant and UPMC Shadyside hospitals. organized and efficient way of delivering cutting-edge health LPI liver team members are liaisons for the management care to patients with complex liver disorders. of complex liver disorders among the regional gastroenterolo- gists, primary care physicians and the multidisciplinary medi- cine and surgery team of the UPMC Liver Pancreas Institute. Dr. Chopra is an Associate Professor of Medicine with the Division of Gastroenterology, Hepatology Areas of clinical expertise and emphasis for the and Nutrition and is the Co-Medical Director for Comprehensive Liver Program focus on the following Liver Transplantation. Dr. Chopra is also Medical disease presentations: Director for the Comprehensive Liver Program with Management of diverse chronic liver diseases the Liver Pancreas Institute. including viral and C, autoimmune diseases, and genetic hemochromatosis;

— Faculty Focus — F ELLOW N EWS

Randall Brand, MD, an internationally The University of Pittsburgh Division of Gastroenterology, recognized expert on Hepatology and Nutrition is pleased to announce familial pancreatic its new Gastroenterology Fellows. cancer and early detection of pancreatic Joining the Division of Gastroenterology, Joseph Rodemann, MD – Loyola cancer and GI , joined Hepatology and Nutrition as Year I University Chicago, Stritch School the Division this autumn. Gastroenterology Fellows are: of Medicine (M), Barnes-Jewish Dr. Brand directs the GI Malignancy Elie Aoun, MD – American University Hospital (R) Early Detection, Diagnosis and of Beirut (M), University of Pittsburgh Vinay Sundaram, MD – New York Prevention Program at UPMC and Medical Center (R) University School of Medicine (M), is academic director for the UPMC Sandra El-Hachem, MD – American University of Virginia Health System (R) Shadyside GI Division (the hospital University of Beirut (M), Cleveland associated with the Hillman Cancer Clinic, Lerner College of Medicine (R) Hepatology Fellow: Center and University of Pittsburgh Anastasios Mavrakis, MD – David Lo, MD – Northwestern Cancer Institute). University of Athens Greece Medical University, Feinberg School of Medi- Dr. Brand’s work will be featured in School (M), Caritas St. Elizabeth’s cine (M), Barnes-Jewish Hospital (R) an upcoming issue of Pitt Digest. Medical Center (Tufts) (R) Shahid Malik, MD – Drexel University College of Medicine (M), University (M) = Medical School of Pittsburgh Medical Center (R) (R) = Residency

Additional information about the University of Pittsburgh Fellowship program may be found at http://www.dom.pitt.edu/gi/fellowship/index.asp 7 What Is This? Presentation: A 35-year-old What’s New in African-American male with a past medical history GI and Hepatology significant for insulin-dependent diabetes mellitus presented with fatigue, shortness of breath and ane- mia (initial hemoglobin = 5.9 g/dL with an MCV = 126.0). An upper endoscopy was performed. Compare your answer to Dr. Ng’s answer on page 6.

Management of Female-Predominant GI Diseases A Rare Complication of Pregnancy November 15 & 16, 2007 continued from page 4 The Duquesne Club • Pittsburgh, Pennsylvania (LCHAD) deficiency found in some cases. Authorities recommend screening all infants born to a mother with Course Directors AFLP for such disorders. David C. Whitcomb, MD, PhD Treatment involves expedited delivery of the fetus and Janet R. Harrison, MD is otherwise largely supportive. The prognosis for AFLP is Kapil B. Chopra good with appropriate treatment, since most patients This activity has been approved for AMA PRA Category 1 Credit™. recover spontaneously after delivery. Yet, in some series, For additional information, contact: maternal mortality approaches 18 percent. Liver disease UPMC/Center for Continuing Education in the Health Sciences severity rarely progresses to necessitate transplantation. Telephone: 412-647-8216 or 412-647-8257 Fetal outcome data is sparse, but fetal mortality has been E-mail: [email protected] quoted at zero to 66 percent, with varying data related to the quality of perinatal care. Typically, this disease does Online registration available at not recur in subsequent pregnancies. http://ccehs.upmc.edu

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