Viral Hepatitis Serology Research Articles

The past and present of serum aminotransferases and the future of liver injury biomarkers.

Laboratory testing is important in the diagnosis and monitoring of liver injury and disease. Current liver tests include plasma markers of injury (e.g. aminotransferases, γ-glutamyl transferase, and alkaline phosphatase), markers of function (e.g. prothrombin time, bilirubin), viral hepatitis serologies, and markers of proliferation (e.g. α-fetoprotein). Among the injury markers, the alanine and aspartate aminotransferases (ALT and AST, respectively) are the most commonly used. However, interpretation of ALT and AST plasma levels can be complicated. Furthermore, both have poor prognostic utility in acute liver injury and liver failure. New biomarkers of liver injury are rapidly being developed, and the US Food and Drug Administration the European Medicines Agency have recently expressed support for use of some of these biomarkers in drug trials. The purpose of this paper is to review the history of liver biomarkers, to summarize mechanisms and interpretation of ALT and AST elevation in plasma in liver injury (particularly acute liver injury), and to discuss emerging liver injury biomarkers that may complement or even replace ALT and AST in the future.

Overlap Syndrome of Autoimmune Hepatitis, Primary Biliary Cholangitis, and Primary Sclerosing Cholangitis in a Patient with Systemic Lupus Erythematosus: A Case Report of Complex Autoimmune Liver Disease

Introduction: Overlap syndrome is a spectrum of clinical manifestations between Autoimmune hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). Overlap syndromes between AIH-PBC and AIH-PSC are well recognized. Overlap between PBC-PSC has only been reported in a few patients. To our knowledge, it is extremely rare for PBC, PSC and probable AIH overlap syndrome to occur in the same patient.Figure 1Figure 2Case report: The patient is a 48-year old Hispanic male with liver cirrhosis and SLE. His cirrhosis was complicated by esophageal varices, thrombocytopenia, coagulopathy, hypoalbuminemia, and chronic portal vein thrombosis. His biochemical profile revealed elevated ALT (2X upper limit of normal (ULN)) and AST (4X ULN), persistently elevated alkaline phosphatase (3X ULN) and elevated bilirubin (2X ULN). Investigations for etiology of cirrhosis included a detailed social history were done. Viral hepatitis serology, iron studies, celiac panel, ceruloplasmin and alpha-1 antitrypsin level were unremarkable. Anti-nuclear antibody (ANA) was positive with a titer of 1:320, anti-smooth muscle antibody (ASMA) was positive with a serum level of 20 (Normally < 20) and P-ANCA was positive. Anti-Soluble liver antigen (anti-SLA) and anti-liver kidney microsomal 1 antigen (Anti-LKM1) were negative. Gamma globulin level was elevated at 2501 mg/dL (normal range 694-1617). Anti-mitochondrial antibody (AMA) was positive with a level of 71.9 units (Normally < 20). The more specific antibody for PBC, AMA-M2, was also positive as well. He also had a positive anti-dsDNA. The patient met criteria for AIH-PBC overlap syndrome based on Paris Criteria. He was on prednisone for autoimmune thrombocytopenia and was started on oral Ursodeoxycholic acid. We also performed an ERCP with cholangiography which showed segmental irregularities of intrahepatic bile ducts with beaded appearance suggestive of sclerosing cholangitis. Based on patient's liver enzymes profile, autoimmune markers, and ERCP findings; he was diagnosed with AIH-PBC-PSC overlap syndrome. We wanted to obtain a liver biopsy, however it could not be done as patient deceased due to septic shock. Conclusion: We are presenting a case with complex clinical spectrum of autoimmune liver diseases which include AIH, PBC, and PSC. To our knowledge, this is only the second reported case of all these diseases overlapping in the same patient; and the first reported case in a patient with SLE.

The Curious Case of a Swollen Belly: Myxedema Ascites

Introduction: Less than 4% of patients with hypothyroidism develop ascites. Ascites as the only presenting feature of hypothyroidism is uncommon, hence diagnosis is often delayed. Once it is diagnosed, treatment of hypothyroidism leads to quick clinical improvement in ascites. We report a case of ascites secondary to severe hypothyroidism.Figure 1Case: A 56 year old female with long standing history of Hashimoto's thyroiditis and non-compliance to thyroid supplementation presented with a four week history of progressive painless abdominal distension. She had recently undergone extensive work-up at a regional hospital. Review of records revealed high ascitic fluid protein content (3.9 g/dl) and serum-ascites-albumin gradient (SAAG) of 1. Ultrasound and computed tomography of the abdomen and pelvis showed massive ascites. Morphology of liver and spleen was unremarkable without any evidence of increased portal pressure. Viral hepatitis serology was negative and tumor markers (CA19-9, CA125) were within normal limits. Hepatic Doppler ultrasound showed normal portal pressure without evidence of portal or hepatic vein thrombosis. We ordered thyroid stimulating hormone level that resulted as >100 units/ml, with low free T4 (0.2 ng/dl). Further evaluation revealed dyslipidemia and mildly elevated alanine and aspartate transaminases and creatine kinase, consistent with thyroid myopathy. The diagnosis of myxedema ascites was made on this diagnostic work-up and the patient was started on thyroid replacement. On a follow-up visit at 4 weeks, there was no clinical evidence of ascites and TSH decreased to 56 units/ml. Discussion: Severe uncontrolled hypothyroidism is a rare but reversible cause of ascites. Various theories have been hypothesized to explain the pathophysiology. These include: 1) an increase in capillary permeability leading to the extravasation of plasma proteins into the extravascular compartment; 2) direct hygroscopic effect caused by hyaluronic acid accumulating in the skin and producing edema; 3) diminished free water clearance due to excess ADH production. Myxedema ascites responds well to thyroid replacement therapy and is completely reversible. Conclusion: Our case illustrates that the diagnosis of myxedema ascites should be borne in mind in a patient with uncontrolled hypothyroidism who presents with ascites. It also signifies the need for testing TSH level as part of the workup for ascites of unknown etiology.

Drug Induced Liver Injury Caused by Lorazepam

This is the case of an 86 year old Hispanic male with medical history significant for dyslipidemia and diabetes mellitus type 2 who arrived to the emergency department due to abdominal pain of 1 month duration. Pain was 5/10 in severity, located in right upper quadrant, with radiation to epigastric region, worst after eating and with associated pruritus, dark urine, pale stools, anorexia and yellow sclera. He denied fever, chills, nausea, vomits, weight loss, early satiety, dysphagia, odynophagia, rectal bleeding or melena. Vital signs stable and physical examination only remarkable for jaundice. Laboratories remarkable for elevated liver enzymes (AST: 244 U/L and ALT: 300 U/L, ALP: 346 U/L and elevated total bilirubin 11.1 mg/dL, with direct predominance). R factor < 2, in favor of cholestatic injury. Toxicology screening and viral hepatitis serology was negative. Ultrasound and CT abdomen failed to show evidence of intra or extra hepatic duct dilatation. MRCP performed with limited findings due to motion blurring. Patient continued with abdominal pain, reason why ERCP was performed. Official report showed no evidence of intra or extra hepatic duct dilation. After above workup performed, a diagnosis of possible Drug Induced Liver Injury (DILI) was entertained. Upon record review and medication reconciliation, patient reported recent use of Lorazepam in view of wife's demise. In view of persistent elevation of hepatic enzymes, liver biopsy of the right lobe was performed. Pathology report revealed moderate lymphocytic infiltrate without evidence of cholangitis, canalicular cholestasis and macrovesicular steatosis (approximately 20%) suggestive of drug-induced etiology. Lorazepam was considered culprit of DILI, with a calculated RUCAM score of 7 (probable). Medication was discontinued and liver function improved markedly. Drug-induced liver injury can develop following the use of many drugs. The mechanism of hepatotoxicity is varied, dose depended or idiosyncratic. Currently it has an estimated annual incidence between 10 and 15 per 10,000 to 100,000 persons exposed to prescription medications and for approximately 10 percent of all cases of acute hepatitis. In the United States, it is the most common cause of acute liver failure. High index of suspicion should be present in patients with these clinical manifestations. A thorough drug history should be taking for all patients as prompt cessation of the offending agent may produce a rapid recovery.

Statin-Induced Liver Injury Mimicking Autoimmune Hepatitis

Introduction: HMG CoA reductase inhibitors (statins) are known to be a cause of hepatic dysfunction, with an incidence of transaminimitis from 0.5 to 3 percent, usually within the first 3 to 4 months of initiating therapy. Here we present a case of acute statin induced liver injury mimicking autoimmune hepatitis. Case Patient is a 70 year old male who initially presented with fatigue, scleral icterus, and a 50 pound weight loss over 3 months. Four months before, he had been started on atorvastatin 40 mg daily which was held on admission. Initial workup showed AST 113 IU/L, ALT 197 IU/L, alkaline phosphatase 944 IU/L (with elevated GGT), and total bilirubin 7.6 g/dL. His INR was 1.15 and creatinine and blood urea nitrogen were 9.53 mg/dL and 121 mg/dL, respectively (no preceding renal dysfunction). Viral hepatitis serologies were negative, and the patient denied any alcohol or acetaminophen use. An MRCP was negative for any biliary obstruction. Urinalysis showed granular casts consistent with acute tubular necrosis. He also had positive smooth muscle antibody, elevated IgG at 2458 mg/dL, positive ANA with 1:1280 titer in a speckled pattern, and positive C-ANCA with a 1:320 titer. P-ANCA, anti-glomerular basement membrane antibody, liver-kidney microsomal antibody, and anti-mitochondrial antibody were negative. Liver biopsy revealed mild mixed portal inflammation and reactive changes with portal fibrosis consistent with a drug reaction, without evidence of autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or hypotensive changes. Kidney biopsy showed mild acute tubulointerstitial nephritis. His AST and ALT also normalized within 3 weeks, to 24 and 38 IU/L, respectively. His alkaline phosphatase improved more slowly, down to 476 IU/L within 3 weeks and total bilirubin improved to 1.3 g/dL. His renal function recovered with supportive care, with creatinine of 0.85 mg/dL within 3 weeks. At outpatient follow up 1 month later, the patient had already gained back 10 pounds, with no residual scleral icterus and improved fatigue. Discussion Statin-associated drug induced liver injury triggering autoimmune hepatitis is rare, with only ten such cases encountered in literature review. These reports often note a liver biopsy consistent with autoimmune hepatitis, which we did not observe. Most cases have required treatment with immunosuppressant medications, while our patient has so far recovered just by holding the statin medication.

Autoimmune Hepatitis Overlap with Primary Biliary Cirrhosis in an HIV Infected Patient

42 year old Hispanic female with HIV on anti-retroviral therapy (ART) since 2009 and polyarthritis referred for evaluation of elevated LFTs. Her only complaint was mild itching of her body. She denied any use of herbal/ dietary supplements, alcohol abuse or illicit drug use. Her exam was unremarkable. Her LFTs were elevated- Alkaline phosphatase 410, AST 213, ALT 153, total bilirubin 0.5 mg/dl. Autoantibody testing showede elevated AMA at 78.6 and ANA titers 1:640. Viral hepatitis serologies including Hepatitis B surface antigen and Hepatitis C RNA PCR were negative. Her iron panel and ceruloplasmin levels were also normal. She was found to have hypergammaglobulinemia with elevated serum IgG levels of 4,117mg/dl (normal IgG less than 1730 mg/dl) and IGg subclass 4 elevated at 264 mg/dl (normal IgG < 86 mg/dl). US Abdomen showed multiple gallstones and gallbladder polyps, CBD was 2 mm and spleen size was normal. Percutaneous liver biopsy was performed and showed highly active portal and lobular hepatitis with evidence of bile duct inflammation and damage consistent with overlap syndrome of autoimmune hepatitis (AIH) with Primary biliary cirrhosis (PBC) and portal and periportal fibrosis with early bridging. Her medications included Hydroxychloroquine & Efavirenz-emtrictabine-tenofovir. Based on her liver biopsy results, patient was started on high dose prednisone 1mg/ kg and Azathioprine with improvement of her LFTs. She was continued on her ART throughout. ‘Overlap’ syndrome is a rare interface between AIH and PBC and is rarely reported in HIV infected adults. The common causes of elevated LFTs in HIV patients include infections and drug induced liver injury secondary to ART. Autoimmune disease in HIV although rare is an important differential while evaluating elevated LFTs in these patients. Unmasking of autoimmune disease is thought to be a manifestation of immune reconstitution with an era of highly effective ART in HIV patients. Our patient was on ART and had a CD4 count >600 suggesting a robust immune system. Her intial chronic liver disease workup suggested autoimmune disease and was confirmed histologically. Early liver biopsy can prevent ART interruption and its related risks. Standard treatment with immune suppressants appears to be effective & safe in HIV patients with high CD4 counts. To the best of our knowledge there is only one other previous case report of biopsy proven overlap syndrome with PBC/AIH in HIV patients.Figure 1Figure 2Figure 3

Pretransplant Hepatitis B Viral Infection Increases Risk of Death After Kidney Transplantation: A Multicenter Cohort Study in Korea.

Clinical outcomes in kidney transplant recipients (KTRs) with hepatitis B virus (HBV) have not been thoroughly evaluated. Here, we investigated recent posttransplant clinical outcomes of KTRs with HBV and compared them with KTRs with hepatitis C virus (HCV) and seronegative KTRs.Of 3855 KTRs from April 1999 to December 2011, we enrolled 3482 KTRs who had viral hepatitis serology data; the patients were followed up for 89.1 ± 54.1 months. The numbers of recipients with HBV and HCV were 160 (4.6%) and 55 (1.6%), respectively. We analyzed the clinical outcomes, including overall mortality and graft failure, among patients who had undergone kidney transplantation.Patients with HBV showed poorer survival (P = 0.019; adjusted hazard ratio [HR] = 2.370; 95% confidence interval [CI]: 1.155-4.865) than KTRs without HBV. However, the graft survival of patients with chronic hepatitis B did not differ from that of patients without HBV. Hepatic complications were the primary causes of mortality of KTRs with HBV. Mortality significantly correlated with a higher grade of inflammation (P = 0.002) and with the use of lamivudine or adefovir antiviral treatment (P = 0.016). HBV-positive KTRs treated with the new-generation antiviral agent entecavir showed improved patient survival compared with KTRs receiving lamivudine (log-rank P = 0.050). HCV did not affect patient survival; however, it increased the incidence of graft failure (P = 0.010; adjusted HR = 2.899; 95% CI: 1.289-6.519). KTRs with HCV had an increased incidence of acute rejection (log-rank P = 0.005, crude HR = 2.144; 95% CI: 1.341-3.426; P = 0.001).KTRs with chronic hepatitis B may exhibit poor survival due to post-transplantation hepatic complications. Pretransplant histological liver evaluations and adequate antiviral management with potent nucleoside/nucleotide analogues are needed to improve the survival of KTRs with chronic hepatitis B even when liver function is within the normal range.

Non-secreting, Non-fibrotic Hepatocellular Carcinoma in an Average Risk Population

Introduction: Hepatocellular carcinoma (HCC) is the fifth leading cancer worldwide. Non-fibrotic HCC (NFHCC) has been fairly reported especially in chronic hepatitis B infection. Nonetheless, recent epidemiological data indicates an overwhelming 12-42% of HCC arising from NAFLD (Non-Alcoholic Fatty Liver Disease) without cirrhosis or fibrosis revealing unexplored thoughts for carcinogenesis. Herein, we present a case of non-secreting NFHCC in an obese male with no apparent risk factors. Methods: We present a 63 year old Caucasian obese male (BMI 35.2 Kg/m2) with no significant past medical history who sustained injuries during a motor vehicle accident. Subsequently, trauma work up was significant for spinal fracture and an incidental right hepatic lesion. On further questioning, the patient denied alcohol abuse, exposure to toxins or family history for GI malignancy. The physical examination was unremarkable as well liver function test, coagulation profile, viral hepatitis serology, anti-nuclear antibody, anti-smooth muscle antibody, iron profile and alpha-fetoprotein(AFP) level. Results: To further investigate the hepatic lesion, a MRI of the abdomen with IV contrast revealed a 3.8 cm heterogenous lesion with ring enhancement suspicious for malignancy and diffuse steatosis otherwise normal biliary tree and pancreatic duct appearance. Malignancy was confirmed by liver biopsy. Subsequent colonoscopy result was benign.Figure 1Figure 2Figure 3After a discussion with the patient and surgery department, the plan was to proceed with surgical resection of the isolated hepatic tumor. The patient successfully underwent a laparoscopic hand-assisted resection of the segment 6 and 7 of the liver. The final surgical pathology confirmed a moderately differentiated HCC with hepatic steatosis. Conclusion: During the last decades, obesity and type 2 diabetes have strongly been associated to NAFLD related NFHCC driven by diverse intrahepatic cellular mechanisms. To the best of our knowledge, the behavior of non-secreting tumors, those lacking AFP, has not been entirely studied in association with NFHCC attributed to NAFLD. Partial resection of liver may be the appropriate option in a good surgical candidate like our patient or in Child-Pugh A cirrotics. If resected timely, a single HCC lesion in minimally to non-fibrotic liver has been reported to have better overall survival irrespective of tumor size. Finally, screening and management of HCC in apparent average risk populations will continue to be a matter of active debate.

Staufferʼs Syndrome: Renal Cell Carcinoma Presenting as Abnormal LFTs

Stauffer's syndrome represents a rare cause of abnormal liver biochemistries. We report a patient who presented with abnormal aminotransferase values and after a comprehensive evaluation was diagnosed with renal cell carcinoma (RCC) as the probable underlying cause. Case: An otherwise healthy and asymptomatic 53-year-old female with no significant past medical history was referred to hepatology for evaluation of persistently abnormal liver tests. There was no personal or family history of liver disease, her weight was stable, she had taken no new medications, she did not consume alcohol or herbal preparations and her viral hepatitis serologies and autoantibodies were negative. Physical examination was normal. Laboratory tests showed mild elevation of liver enzymes that had only been noted for the last year, and were previously normal, with a peak alanine aminotransferase (ALT) of 106 IU/L and peak aspartate aminotransferase (AST) of 60 IU/L. An abdominal ultrasound was obtained that showed diffuse echogenicity most likely consistent with diffuse hepatic fatty infiltration and incidentally revealed a 12 cm enhancing mass arising from the lower pole of the left kidney suspicious for RCC. She subsequently underwent successful nephrectomy with pathology demonstrating a chromophobe variant of RCC. No hepatic metastasis or main bile duct obstruction were detected by abdominal computed tomography. Her liver function test abnormalities normalized one month post-operatively. Discussion: Stauffer's syndrome was reported in 1961 as “nephrogenic hepatomegaly” and is characterized by elevated liver function tests in the absence of metastatic disease, raised erythrocyte sedimentation rate, and occasionally jaundice. Prolongation of the prothrombin time and hepatosplenomegaly may also be seen. An important differential diagnosis is liver metastasis as an underlying etiology. Malignant diseases may cause jaundice through either main bile duct obstruction or widespread metastasis to the liver. RCC causes various paraneoplastic manifestations, which can be the main presenting symptoms. Hepatic dysfunction, in absence of liver metastases, occurs in 10 to 15% of patients with RCC, attributed to the production of cytokines from the tumor cells, including interleukin-6. Conclusion: Stauffer's syndrome is a rare paraneoplastic manifestation of RCC. We present variant case of probable Stauffer's syndrome with resolution of otherwise unexplained liver biochemistries after the patient underwent nephrectomy to resect a chromophobe RCC. The case also highlights the benefits of abdominal ultrasound early in the course of routine evaluation of abnormal LFTs.Figure 1

Goldenseal Root Powder (Hydrastis Canadensis) Associated Hepatotoxicity

Introduction: The use of herbal supplements has increased in the United States in last decade. It may be associated with significant side effects. We report a patient with hepatotoxicity following ingestion of herbal preparation, Goldenseal root powder. Case report: A 60-year-old female was admitted to the hospital with delusional behavior. A family member had recently noticed that she was jaundiced. The patient had no prior history of liver disease. Her past medical history was significant for paranoid schizophrenia and diabetes mellitus. She denied taking any medication apart from goldenseal root powder for four months prior to admission, for general wellbeing. She did not smoke or drink alcohol. There was no history of drug abuse. Her physical examination was unremarkable apart from icteric sclera. Her liver function test showed total bilirubin of 18.8 mg/dL, direct bilirubin 11.8 mg/dL, aspartate transaminase (AST) 94 U/L, alanine transaminase (ALT) 76 U/L, alkaline phosphatase 1832 U/L, albumin 2.4 g/dL, and INR 1.0. An abdominal computed tomography (CT) and liver ultrasound showed hepatomegaly without signs of cholecystitis or extra hepatic obstruction. Viral hepatitis serology, antinuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, liver/kidney microsome antibodies, ceruloplasmin level, and iron panel were normal. A liver biopsy showed cholestasis with canalicular and intraductular bile plugs, compatible with drug-induced cholestatic hepatitis. The patient's jaundice improved while in the hospital. Patient was instructed to stop using goldenseal root powder. Outpatient follow-up showed continued improvement in her liver function test. Discussion: Herbal medicines are widely perceived by the public as an innocuous health aid. Goldenseal root powder is thought to be hepatoprotective in animal models by inhibiting CYP2E1 enzyme.1 However, some herbal medicines may be associated with hepatotoxicity. Our patient's liver function improved after discontinuation of goldenseal root powder and no other etiology of cholestatic hepatitis was identified. This appears to be the first case report in english literature on goldenseal root powder associated hepatotoxicity. Our case highlights that hepatotoxicity should be considered in anyone taking goldenseal root powder.

A Case of Over-the-Counter, Drug-Induced Autoimmune Hepatitis: Immunohistochemical and Electron Microscopic Studies

Introduction: In daily clinical practice, drug-induced liver injury(DILI) can always be a cause of liver injury in patients taking medications. Over-the-counter(OTC) drug: Pabron has been purchasing at the pharmacy in Japan, Thailand, Malaysia, and Chinese Taipei as a multi-component cold medicine. We desribed a case of DI-autoimmune hepatitis(AIH) from OTCdrug: Pabron gold®. Case description: A 64-year-old man sought treatment for common cold and was admitted for general fatigue and liver dysfunction. Blood test results included total bilirubin (T-bil), 2.4 mg/dL; direct bilirubin (D-bil), 1.4 mg/dL; AST, 1,244 IU/L; ALT 1,455 IU/L; ALP 1,242 IU/L; and γ-GTP 599, IU/L. Viral hepatitis serology was negative. Other relevant data included IgG level, 1,907 mg/dL; IgM, 95 mg/dL; ANA x80 (cut-off, < x40); ASMA x20 (cut-off, OTC, namely Pabron Gold®, prior to disease onset which was suspected as the cause of liver injury. A DI lymphocyte stimulation test for Pabron Gold® was positive, 2,447 cpm (503%) (< 179%). The liver biopsy revealed spotty necrosis and the accumulation of ceroid pigment in Kupffer cells around central vein, and piecemeal necrosis with multiple plasma cells around portal tracts. Moreover, the plasmocytic infiltration showed positive CD79a staining while negative CD20 staining. Ultrastructually, “cart-wheel” chromatin configuration in the nucleus was observed in some of plasma cells packing with a lot of rough-surfaced endoplasmic reticulum. Moreover, the characteristic granular osmiophilic materials and lipid droplet were observed in Kupffer cell. HLA typing test was HLA-DR4 positive. The score based on simplified criteria for autoimmune hepatitis diagnosis was 6, probable. With a persistent rise in aminotransaminase levels, the patient was started on steroids with predonine prescribed to control the hepatic inflammation. Discussion: This report is the first to describe a case of DI-AIH following the use of an over-the-counter drug. In fact, DI-AIH diagnosis represents a challenge to the clinician because neither histological nor clinical pathognomonic features of AIH exist. We described a case of OTC Pabron gold®-associated liver injury, diagnosed as DI-AIH, calling for caution in the use of OTC.

Obliterative Portal Venopathy Masquerading Large Bile Duct Obstruction in a Patient on Oral Contraceptive Pills

Introduction: Oral contraceptives pills (OCP) are generally safe but can cause wide range of side effects. We report a case of obliterative portal venopathy (OPV) causing large bile duct obstruction picture from OCP use and slow resolution after discontinuation of the medication. Case: A 19-year-old woman with medical history of Down's syndrome and hypothyroidism presented with acute jaundice, pruritus and RUQ abdominal pain. She denied any fever, alcohol use, recent travel, sick contacts, new medications or herbal supplements. Her medications included levothyroxine, fexofenadine and OCP. Physical exam was remarkable for icterus and RUQ tenderness with positive Murphy's sign. Labs showed a total bilirubin of 8.0 with direct bilirubin of 5.1, alk phos of 245, AST of 50, ALT of 100 and lipase of 23. Acute and chronic hepatitis work up was negative for acetaminophen toxicity, viral hepatitis, EBV, CMV and HSV serologies, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, α1 antitrypsin deficiency, and HIV. Urine toxicology was negative. Ultrasound showed no evidence of cholecystitis, cholelithiasis or choledocholithiasis. There was no intra or extra hepatic biliary obstruction on EUS and MRCP. CT scan was unremarkable. Alk phos progressively increased to 500 and the bilirubin slowly improved. The liver biopsy showed histologic features of large bile duct obstruction, and features suggestive of OPV and nodular regenerative hyperplasia. This was most likely thought to be due to OCP use in the absence of other etiologies. OCP was discontinued and LFT's slowly improved with normalization in 5 months. Discussion: OCPs are currently prescribed to 62 million women of reproductive age in the US. While deemed mostly safe, they can cause hepatic and biliary dysfunction, and a small subset of women develop intrahepatic cholestasis. Liver biopsy shows bland cholestasis without significant inflammation. Obstructive picture with OPV has not been described. A prothrombotic state caused by OCP probably resulted in OPV-induced large duct injury and obstruction picture in the biopsy. This report highlights that OCP can present with OPV and secondary changes such as large duct injury due to their prothrombotic effects. OPV should be considered as a differential diagnosis if the labs and biopsy show findings suggestive of large bile duct obstruction before proceeding with invasive procedures like ERCP.

Clinical and epidemiological profile of female blood donors with positive serology for viral hepatitis B.

Since women are frequently the minority among blood donors worldwide, studies evaluating this population usually reflect male features. We assessed the features of female blood donors with positive serology for HBV and compared them with those of men.METHODS The study comprised consecutive blood donors referred to a specialized liver disease center to be evaluated due to HBsAg- and/or anti-HBc-positive tests. The study encompassed 1,273 individuals, 219 (17.2%) of whom were referred due to positive HBsAg test and 1,054 (82.8%) due to reactive anti-HBc test. Subjects' mean age was 36.8±10.9 years, and 28.7% were women. Female blood donors referred for positive HBsAg screening tests demonstrated higher prevalence of healthcare workers (9.3% vs 2.5%) and lower prevalence of sexual risk behaviors (15.1% vs 41.1%) and alcohol abuse (1.9% vs 19.8%) compared to men. Women had lower ALT (0.6 vs 0.8×ULN), AST (0.6 vs 0.8×ULN), direct bilirubin (0.2 vs 0.3mg/dL), and alkaline phosphatase (0.5 vs 0.6×ULN) levels and higher platelet count (223,380±50,293 vs 195,020±53,060/mm3). Women also had a higher prevalence of false-positive results (29.6% vs 17.0%). No differences were observed with respect to liver biopsies. Female blood donors referenced for reactive anti-HBc screening tests presented similar clinical, epidemiological, and biochemical characteristics to those reported for positive HBsAg screening tests and similarly had a higher prevalence of false-reactive results. Compared to men, female blood donors with positive HBsAg and/or anti-HBc screening tests demonstrated higher prevalence of professional risk and false-positive results and reduced alteration of liver chemistry.

Association of aplastic anaemia with positive viral hepatitis serology, and its outcome after immunosuppressive therapy

s / Journal of Clinical Virology 69 (2015) 223–246 241 advocacy by comparison with other infectious diseases. TheWorld Health Organization supports the development of national strategic approaches. The aim of this study was to provide evidence for developing coordinated policy responses by investigating the elements of the public policy response to chronic viral hepatitis in Taiwan to inform best practice. Methods: The policy assessment reviewed literature and conducted semi-structured qualitative interviews with key participants and interested partners in the national response to chronic viral hepatitis in Taiwan. These participants (n=26) included clinicians, government officials, advocates, representatives from non-governmental organisations, and pharmaceutical companies and were conducted in Taiwan in June, 2013. Findings: Taiwan implemented a public policy response to viral hepatitis through a series of 5-year plans commencing from 1982. Initially, this response provided the framework for the world’s first comprehensive hepatitis B vaccination programme, and over time incorporated interventions to improve access to clinical services and to reduce the burden related to hepatitis C infection. Interpretation: Critical factors in Taiwan’s response are an effective health-service delivery architecture, an acceptance of the need for disease prevention, government promotion and funding of science and technology, and a rigorous evidence base with sustained advocacy. http://dx.doi.org/10.1016/j.jcv.2015.06.055

Haloperidol-induced Cytolytic Hepatitis

Introduction Contrary to phenothiazines, butyrophenones are very seldom associated with hepatitis. In particular, the incidence of hepatitis on haloperidol is about 0.002%. Almost all these cases consisted of cholestatic hepatitis. Cytolytic hepatitis induced by haloperidol seems to be exceptional. Objective To outline the occurrence of haloperidol-induced cytolytic hepatitis. Methods Case report and review Results We report the case of a male patient aged 22, with a family history of schizophrenia in two cousins and with a personal history of generalized epilepsy on carbamazepine. The patient was admitted to our department for behavioral disturbances. Psychiatric interview found mystical and grandiosity delusions as well as auditory and visual hallucinations. The patient was started on haloperidol 5mg bid. Routine liver enzymes obtained on day-10 revealed eight-fold elevated transaminases with no associated biological signs of cholestasis. The patient did not report any symptoms suggestive of hepatitis. Serology for viral hepatitis (A, B, and C), EBV and CMV was negative. Hepatic ultrasound examination was normal. Antinuclear, anti-LMK and anti-mitochondrial antibodies were negative. Serum and urine copper levels were normal. The diagnosis of a drug-induced hepatitis was made. Haloperidol was withdrawn and switched to olanzapine. Transaminase levels slowly dropped then normalized within two months, thus consolidating our diagnosis. Conclusions Cytolytic hepatitis induced by haloperidol is very rare and can be asymptomatic. Routine liver tests when starting antipsychotics are crucially important to diagnose this possibly hazardous side effect.

Unusual Cause of Bilateral Pleural Effusion.

Unusual Cause of Bilateral Pleural Effusion.

Thyroid Storm Presenting With Profound Cholestatic Liver Injury: A Rare Diagnostic Dilemma

Introduction: Thyrotoxicosis from Graves disease can cause multi-organ dysfunction including abnormal liver function tests. Severe cholestatic liver injury directly caused by thyroid storm is rare, and can pose a diagnostic dilemma with etiologies such as congestive heart failure, drug-induced liver injury, concurrent primary biliary cirrhosis (PBC), or autoimmune hepatitis (AIH) being more common. We report an unusual case of thyroid storm-induced profound cholestatic liver injury mimicking PBC and AIH overlap syndrome. A 35-year-old female with an unremarkable past medical history presented to a local hospital with a 2-day history of jaundice and pruritus. Physical examination was significant for thyromegaly and right upper quadrant abdominal tenderness. Liver function tests revealed aspartate aminotransferase (AST) of 1935 unit/L, alanine aminotransferase (ALT) of 982 unit/L, alkaline phosphatase of 484 unit/L, total bilirubin (TB) of 21.6 mg/dL, direct bilirubin (DB) of 16.3 mg/dL, INR of 1.8, and a high gammaglobulin (IgG) level. A liver biopsy showing moderate mixed portal and lobular inflammation, bile duct injury, and focal ductular reaction was interpreted as PBC and AIH overlap syndrome. She was discharged after clinical improvement on prednisone. She presented to our hospital 5 days later with new onset tachycardia of 120 beats per minute, thyroid bruit, diffuse abdominal tenderness, and resting tremor. Laboratory data showed improved but abnormal AST, ALT, and INR, and increased TB of 31.1 mg/dL and DB >20.0 mg/dL. Viral hepatitis serologies, antimitochondrial antibody, anti-liver-kidney microsomal antibody, antinuclear antibody, and anti-smooth muscle antibody were negative. IgG level normalized. Her thyroid stimulating hormone (TSH) was <0.01 mcIU/mL and free thyroxine (FT4) was 5.9 ng/dL. TSH receptor antibodies and thyroid stimulating immunoglobulin were positive, suggestive of thyroid storm secondary to Graves disease. A CT scan of the abdomen and transthoracic echocardiogram were grossly normal. Potassium iodide was promptly started. On hospital day 8, she underwent a thyroidectomy given limited medical options. Three weeks after FT4 normalized, her liver function tests also returned to normal. This case demonstrates that in the absence of autoantibodies, hepatotoxic medication, and congestive heart failure, thyrotoxicosis can be a direct cause of severe cholestatic liver injury. It can also produce inflammatory changes and bile duct injury typical of PBC or AIH overlap syndrome. Special attention should be paid to thyroid abnormalities, since early recognition is of paramount importance and appropriate treatment can reverse the hepatic injury, as seen in our case.

Blurry Vision in Patient With Watery Diarrhea: Serendipitous Diagnosis of Neurocysticercosis

Introduction: Neurocysticercosis, also known as disease of swine, is a common helminthic infection estimated to occur in 50,000 people worldwide. In 2013, 148 cases from United States were reported to the WHO. Humans become intermediate hosts of Taenia solium by ingesting its’ eggs from contaminated food specially undercooked pork. Common presentations of gastrointestinal involvement are abdominal pain, nausea, diarrhea or constipation which arise within 6-8 weeks after cyst ingestion. Neurologic symptoms including headaches and seizures may precede GI symptoms. A 26-year-old Guatamalan male without past medical history had lived in the U.S. for 13 years. He had not traveled abroad during this period. He was evaluated in the ED for a 3 day history of severe headaches, nausea, nonbloody emesis and watery diarrhea. Symptoms accompanied by blurry vision. On enquiry, he had suffered from headaches for over 2 years but these had not been associated with visual symptoms, fever, back pain, paresthesias, seizures, or a skin rash. He did not have recent exposure to sick contacts or animals. Physical examination including neurologic and fundoscopic exams were unremarkable except for mild diffuse abdominal tenderness. Laboratory data including CBC, CMP, ESR, HIV and viral hepatitis serologies, urine toxicology were all negative. Head CT scan detected low attenuation in the paramesencephalic cistern, along the basilar cisterns and extending into the left sylvian fissure reported as suspicious for gelatinous pseudocysts of cryptococcal meningitis. MRI imaging showed cerebral calcifications with multiple cystic lesions with widening of the left sylvian fissure and prominent lateral ventricle with the floor of the third ventricle depressed into the sella turcica suggesting a communicating hydrocephalus secondary to racemose neurocysticercosis. Serum ELISA for cysticercus antibody was weakly positive (>0.90). Stool tests were negative for ova and parasites. Cryptococcal antigen was negative. Dexamethasone, albendazole and antiseizure prophylaxis medications were initiated to treat neurocysticercosis. At two month follow up, patient was doing well with resolution of GI symptoms and improved vision. Taeniasis continues to be a serious public health problem especially in patients from Mexico, Guatemala and Peru. A high index of suspicion for neurocysticercosis is important in patients from these endemic areas who present with persistent GI and neurologic symptoms. In addition to praziquantel or albendazole, neurocysticercosis treatment includes supportive therapy with corticosteroids and seizure prophylaxis. Taeniasis is one of the top neglected tropical diseases of this decade whose eradication is a current challenge of the WHO.

Nodular regenerative hyperplasia in a patient with generalized essential telangiectasia: Endotheliopathy as a causal factor

A 60-year-old Caucasian man was referred to the outpatient clinic for evaluation of splenomegaly. The patient's history revealed only a noninsulin-dependent diabetes mellitus and a generalized essential telangiectasia (GET), which developed over the past 20 years with extensive telangiectasias primarily on the arms, legs, and trunk (Fig. 1A). Face and oral/nasal mucosa were spared, epistaxis was denied, and family history of telangiectasias was absent, which clearly distinguishes GET from hereditary hemorrhagic telangiectasia (HHT). The patient stated occasional wine consumption; viral hepatitis and autoimmune serologies were negative. Abdominal ultrasound revealed splenomegaly and a recanalized umbilical vein. Upper gastrointestinal endoscopy showed portal-hypertensive gastropathy (Fig. 1B) and grade II esophageal varices (Fig. 1C), as further evidence of portal hypertension. Prominent mucosal vasculature and angiectatic vessels were found throughout the small and large intestine (Fig. 1D). Transjugular measurement of the hepatic venous pressure gradient (HVPG) was surprisingly normal with a gradient of 4 mmHg, suggesting a prehepatic or presinusoidal form of portal hypertension. Correspondingly, liver biopsy revealed nodular regenerative hyperplasia (NRH) with grade 3 nodularity and megasinusoids (arrowheads, Fig. 1F) in the absence of fibrosis. Hepatic plates were compressed by dilated sinusoids and regenerating hepatocytes, resulting in the typical nodular appearance characteristic for NRH. The patient showed progression to grade III esophageal varices despite treatment with propranolol and developed refractory ascites. Therefore, it was decided to place a transjugular intrahepatic portosystemic shunt (TIPS). During TIPS placement, invasively measured portal pressure was severely increased to 30 mmHg, which was reduced to a portal pressure of 10 mmHg after TIPS placement. Follow-up showed reduction of varices and resolution of ascites. Although the pathogenesis of NRH is not fully understood, a growing body of evidence based on autopsy studies and multiple case series indicates that NRH is the response to impaired hepatic blood supply.1 These hemodynamic changes can be due to thrombotic events or endothelial injury of the microvasculature. NRH has been described in association with vascular disorders, i.e., polyarteritis nodosa, rheumatoid vaculitis, or HHT,2, 3 providing further evidence that an endotheliopathy is a causative factor inducing secondary changes of the liver architecture leading to NRH. Systemic vascular diseases can directly lead to impaired hepatic blood flow through vascular stenosis after endothelial changes/injury or indirectly by causing obliteration due to thrombi generation. GET is another endotheliopathy characterized by widespread telangiectasias with primarily cutaneous involvement, whereas internal organs are usually not affected. Here we describe for the first time a patient with NRH in association with the vascular disorder GET. The availability of a liver biopsy for molecular analysis from our patient allowed measuring messenger RNA (mRNA) expression levels of genes that are known to regulate endothelial differentiation. In comparison to controls,4 we observed a down-regulation of Notch1, Dll4, EphrinB2, and Tek in our patient (Fig. 1F). These genes have recently been shown to be implicated in the process of vascular remodeling in a murine model displaying features of NRH after deletion of Notch1.5 NRH occurred as a secondary event following activation of the sinusoidal endothelium, with ensuing vascular dedifferentiation and intussusceptive angiogenesis. Furthermore, down-regulation of the same set of genes was confirmed in NRH patients.4 Thus, also on the genetic level, endothelial involvement in the pathogenesis of NRH was proven in the presented case. In conclusion, we describe the first case of NRH in a patient with general essential telangiectasia. Our findings suggest that NRH is the hepatic manifestation of this systemic endotheliopathy. Molecular analysis showing dysregulated Notch, Ephrin, and Tek signaling is in line with the recent description in a murine NRH model, further strengthening the hypothesis that NRH is driven by a vascular disorder.

A Rare Cause of Chronic Diarrhea and Weight Loss

A78-year-old woman was evaluated for fatigue, unintentional weight loss of 38 pounds, and diarrhea over the past year. She appeared in no acute distress. Her blood pressure was 120/80 mm Hg and her heart rate was 76 beats/min. She was 61 inches tall and weighed 96 pounds, with a body mass index of 18 kg/m. An abdominal examination was significant for mild epigastric tenderness to palpation. The patient would have approximately 7 nonbloody watery bowel movements during the day with occasional nocturnal diarrhea. Her bowel movements were not affected by fasting. She had associated lower abdominal pain and intermittent epigastric pain. Prior work-up included negative stool studies for Clostridium difficile, ova and parasites, culture, and Gram stain. Laboratory studies showed a normal hemoglobin level, mean corpuscular volume, thyroid-stimulating hormone level, alanine aminotransferase level, total bilirubin level, albumin level, and C-reactive protein level. She had an abnormal alkaline phosphatase level of 130 IU/L (38–126 IU/L), an aspartate aminotransferase level of 52 IU/L (15–41 IU/L), a g-glutamyl transpeptidase level of 49 IU/L (<41 IU/L), and a lipase level of less than 3 U (15–70 U/L). A colonoscopy and upper endoscopy showed no gross or histologic evidence of malignancy, celiac disease, or microscopic colitis. A contrast-enhanced computed tomographic scan of the abdomen and pelvis showed cirrhosis, an obstructing distal pancreatic duct calculus, and complete fatty replacement of the pancreas, which was highly suggestive of lipomatous pseudohypertrophy (Figure A). An endoscopic ultrasound was performed and confirmed the diagnosis and excluded an underlying pancreatic adenocarcinoma (Figure B). The patient denied alcohol use. Viral hepatitis serologies, iron saturation level, ceruloplasmin level, autoimmune serologies, and a-1 antitrypsin level all were normal. The most likely etiology of the patient’s cirrhosis was nonalcoholic steatohepatitis. The patient denied previous episodes of pancreatitis, but the presumptive etiology of the distal pancreatic duct calculus was chronic pancreatitis. Pancreatic enzyme replacement therapywas initiated and the patient reported resolution of her symptoms 2 days later. At our patient’s follow-up visit 1 month after initiation of pancreatic enzyme replacement therapy, her weight increased to 101 pounds and her symptoms resolved. Lipomatous pseudohypertrophy is a rare idiopathic clinical entity that has been described only in case reports and case series. Based on a small case series and literature review, Altinel et al determined that this condition occurs with equal frequency in males and females, with approximately 70% of cases diffusely involving the pancreas. Histologically, adipose pseudotumor replacement of pancreatic exocrine tissue is seen. Because of its low prevalence, the etiology of lipomatous pseudohypertrophy has yet to be determined. Varying presentations have been described including large pancreatic tumors subsequently diagnosed as lipomatous