title: Hirmi Valley liver disease: a disease associated with exposure to pyrrolizidine alkaloids and DDT.
abstract: OBJECTIVE
  Hirmi Valley liver disease was first reported in 2001 in Tigray, Ethiopia. 591 cases, including 228 deaths, were reported up to December 2009. The pyrrolizidine alkaloid acetyllycopsamine was detected in stored grain and residents reported adding the pesticide DDT (dichlorodiphenyldichloroethylene) directly to their food stores. We aimed to characterise the clinical features of the disease, and explore the role of these chemicals in its aetiology.
  
  
  METHODS
  32 cases were examined and full clinical histories taken. Nine cases underwent liver biopsy in hospitals. Serum and urine samples were collected from cases and controls. Urine was analysed for acetyllycopsamine by UPLC-MS. Total DDT in serum was measured by ELISA. Hepatotoxicity of DDT and acetyllycopsamine alone or in combination was explored in C57BL/6J mice.
  
  
  RESULTS
  Clinical presentation included epigastric pain, abdominal swelling, bloody diarrhoea, hepatomegaly, splenomegaly, and ascites. Histology revealed acute injury characterised by centrilobular necrosis or chronic injury with bile ductular reaction, cytomegaly and fibrosis but no hepatic vein occlusion. Acetyllycopsamine was detected in urine samples taken in the affected area with significantly greater concentrations in 45 cases than in 43 controls (p=0.02). High levels of DDT (>125 ppb) were detected in 78% of serum samples. In mice, DDT (3 × 75 mg/kg) significantly increased the hepatotoxicity (plasma ALT, p=0.0065) of acetyllycopsamine (750 mg/kg), and in combination induced liver pathology similar to Hirmi Valley liver disease including centrilobular necrosis and cytomegaly.
  
  
  CONCLUSIONS
  This novel form of disease appears to be caused by co-exposure to acetyllycopsamine and DDT.
authors: School of Public Health, Imperial College London, UK; Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors: Oliver
authors: O
authors: Robinson
authors: Department of Surgery & Cancer, Imperial College London, UK.
authors: Elizabeth
authors: E
authors: Want
authors: Department of Surgery & Cancer, Imperial College London, UK.
authors: Muireann
authors: M
authors: Coen
authors: Abraham's Oasis, Shire, Ethiopia.
authors: Ruth
authors: R
authors: Kennedy
authors: Abraham's Oasis, Shire, Ethiopia.
authors: Catharina
authors: C
authors: van den Bosch
authors: Tigray Health Bureau, Mekele, Ethiopia.
authors: Yohannes
authors: Y
authors: Gebrehawaria
authors: Department of Medicine, Imperial College London, UK.
authors: Hiromi
authors: H
authors: Kudo
authors: Department of Medicine, Imperial College London, UK.
authors: Fouzia
authors: F
authors: Sadiq
authors: Department of Medicine, Imperial College London, UK.
authors: Robert D
authors: RD
authors: Goldin
authors: School of Public Health, Imperial College London, UK; Onehealth Foundation, Switzerland.
authors: Michael L
authors: ML
authors: Hauser
authors: School of Public Health, Imperial College London, UK.
authors: Alan
authors: A
authors: Fenwick
authors: School of Public Health, Imperial College London, UK.
authors: Mireille B
authors: MB
authors: Toledano
authors: Department of Medicine, Imperial College London, UK. Electronic address: m.thursz@imperial.ac.uk.
authors: Mark R
authors: MR
authors: Thursz
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003634:DDT / Q000097:blood / Q000633:toxicity*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*
chemical_list: D011763:Pyrrolizidine Alkaloids; D003634:DDT; D000469:Alkaline Phosphatase
keywords: AL; ALP; ALT; AST; Acetyllycopsamine; DDT; EHNRI; ELISA; Enzyme Linked Immunosorbent Assay; Ethiopia; Ethiopian Health and Nutrition Research Institute; GGT; H&E; HVLD; Hepatotoxicity; Hirmi Valley liver disease; PA; THB; Tigray Health Bureau; ULN; UPLC-MS; Ultra performance liquid chromatography – mass spectroscopy; VOD; acetyllycopsamine; alanine transaminase; alkaline phosphatase; aspartate transaminase; cyp3a; dichlorodiphenyldichloroethylene; gamma glutamyl transferase; haematoxylin and eosin; pyrrolizidine alkaloid; upper limit of normal of the laboratory reference range; veno-occlusive disease