Polyvinylpyrrolidone deposition disease : The role of pathology in understanding disease and death in persons with opioid addiction and intravenous drug use

Bakgrunn og målsetting: Polymeren polyvinylpyrrolidon (PVP) er mye brukt som tilsetningsstoff i legemidler. PVP med høy molekylvekt kan ikke utskilles via nyrene og vil derfor opphopes i kroppens vev dersom det administreres parenteralt. I 2013 oppdaget patologer ved Haukeland universitetssykehus tilfeller av PVP-avleiring i vevsprøver fra pasienter med opioidavhengighet og intravenøs rusbruk. En av legemidlene som på den tiden ble brukt i legemiddelassistert rehabilitering (LAR) var en metadonsirup ment for oral bruk som inneholdt PVP med svært høy molekylvekt (PVP K90). Man mistenkte at intravenøs bruk av denne metadonsirupen var årsaken til PVP-avleiring hos pasientene. Denne oppdagelsen førte til at metadonsirupen ble trukket fra markedet i Norge og i EU, og var utgangspunktet for prosjektet som denne doktorgraden er basert på. Hovedmålsettingen for doktorgraden var å studere de patologiske funnene hos pasienter med PVP avleiringssykdom etter injeksjon av PVP-holdige legemidler for opioidsubstitusjon og å vurdere de kliniske konsekvensene. Metoder: Studiene baserer seg i hovedsak på grundig kvalitativ og kvantitativ evaluering av vevsprøver tatt i diagnostisk øyemed og ved obduksjoner samt vurdering av de patologiske funnene opp mot kliniske data. Resultater: Denne graden handler om de patologiske og kliniske funnene i 33 pasienter med PVP-avleiringssykdom. Alle biopsier og obduksjonsprøver viste PVP-avleiringer som i noen tilfeller var svært utbredt. Funnene tyder sterkt på at PVP-avleiring har forårsaket alvorlig anemi, patologiske beinbrudd og kronisk nyresykdom. Hos to pasienter forårsaket PVP-avleiringer sannsynligvis dødelig utfall. Konklusjon: Intravenøs bruk av en metadonsirup som var ment for oral bruk, og som inneholdt PVP K90 som tilsetningsstoff, har forårsaket PVP-avleiringer hos ruspasienter. I noen tilfeller er det sannsynlig at dette har forårsaket alvorlig sykdom og død. Denne graden fremhever viktigheten av en grundig patologisk evaluering av vevsprøver og den viser hvordan melding om mulige bivirkninger, selv fra patologer, kan utgjøre en stor forskjell for pasientene. Den viser også hvordan velmente forsøk på å hindre uønsket bruk av medisiner kan få uønskede konsekvenser.Background and aims: The polymer polyvinylpyrrolidone (PVP) is commonly used as an excipient in drugs. Parenterally administered high molecular weight PVP cannot be excreted, and therefore accumulates in tissues, resulting in PVP deposition. In 2013, pathologists at Haukeland University Hospital discovered cases of PVP deposition in tissue samples from patients with opioid addiction and intravenous drug use (IVDU), most of whom were enrolled in the opioid substitution therapy (OST) program in Norway. Intravenous injection of a specific opioid substitution drug, an oral methadone syrup containing very high molecular weight PVP (PVP K90) was the suspected cause of PVP deposition in these patients. This discovery eventually led to the withdrawal of this methadone syrup from the market in Norway and the European Union (EU) and was the origin of the project on which this thesis is based. The main objective of this thesis was to study the pathological findings in patients with PVP deposition disease from injection of PVP-containing opioid substitution drugs and to assess the clinical consequences. Methods: The principal methods used in the studies were thorough qualitative and quantitative evaluations of histological specimens collected for diagnostic purposes and at autopsies. The pathological findings were then correlated with clinical data. Results: This thesis discusses the pathological and clinical findings of 33 patients with PVP deposition. All biopsies and autopsy samples revealed PVP deposits, and in some patients, PVP deposition was very extensive. The findings strongly indicate that PVP deposition has caused severe anemia, pathological fractures and chronic kidney disease. In two patients, PVP deposition likely caused the fatal outcome. Conclusions: Intravenous use of an oral methadone syrup containing PVP K90 has led to PVP deposition in patients with opioid addiction and IVDU, in some patients likely resulting in severe disease and fatal outcome. This thesis underscores the importance of a thorough pathological investigation of tissue samples and shows how reporting potential adverse drug reactions, even by pathologists, can make a big difference for patients. It also shows how well intended efforts to prevent unintended uses of drugs can have unwanted consequences.Doktorgradsavhandlin

Chronic Kidney Disease from Polyvinylpyrrolidone Deposition in Persons with Intravenous Drug Use

Background and objectives Persons with intravenous drug use have a higher risk of developing CKD compared with the general population. In Norway, deposits of polyvinylpyrrolidone have been observed in kidney biopsies taken from persons with opioid addiction and intravenous drug use since 2009. Polyvinylpyrrolidone is an excipient commonly used in pharmaceuticals, and the polyvinylpyrrolidone deposits observed in these patients were caused by intravenous injection of a specific oral methadone syrup containing very high molecular weight polyvinylpyrrolidone. Here, we present the clinicopathologic findings from 28 patients with CKD associated with polyvinylpyrrolidone deposition in the kidney. Design, setting, participants, & measurements The 28 patients and their kidney biopsies were included when polyvinylpyrrolidone deposition was recognized, either retrospectively or at the time of diagnostic evaluation. Biopsies were taken between 2009 and 2016. We collected laboratory parameters and clinical data from digital patient charts. For each kidney biopsy, the glomerular volume, extent of polyvinylpyrrolidone deposition, and tubulointerstitial area with tubular atrophy were assessed quantitatively. Results All patients (mean age: 37 years) had CKD (mean eGFR: 33 ml/min per 1.73 m2) and normal urine protein or non-nephrotic–range proteinuria. Biopsies showed moderate to severe tubular atrophy (mean extent: 65%) and interstitial infiltrates of vacuolated macrophages containing polyvinylpyrrolidone (mean share of biopsy area: 1.5%). Underperfused and ischemic glomeruli were common findings. In 22 samples, ultrastructural investigation revealed polyvinylpyrrolidone-containing vacuoles in the mesangial or endothelial cells of glomeruli. At the last follow-up, most patients had stable or improved eGFR. Two patients had developed kidney failure and underwent hemodialysis. Conclusions Intravenous injection of a specific oral methadone syrup caused polyvinylpyrrolidone deposition in the kidney in persons with opioid addiction and intravenous drug use. Kidney biopsy findings suggested an association between polyvinylpyrrolidone deposition and tubular atrophy.acceptedVersio

Polyvinylpyrrolidone deposition disease in patients with intravenous opioid use: a case series

The polymer polyvinylpyrrolidone (PVP) is an excipient widely used in prescription drugs. Depending on the molecular weight (MW), parenterally administered PVP may accumulate in various tissues. Consequently, moderate and high MW PVP have only been used in oral preparations since the late 1970s. Surprisingly, starting in 2009, pathology departments in Norway received biopsies revealing PVP deposition, all from patients with a history of intravenous drug use. We identified 13 patients with PVP deposition and re-evaluated 31 biopsies and two autopsies. Common indications for biopsy were renal insufficiency, anemia, pathological fractures, and abdominal complaints. We observed PVP deposits in all biopsies (kidney, hematopoietic bone marrow, bone, gastrointestinal tract, lymph node, and skin) and all sampled tissue from the autopsies. Overall, the clinical findings could be related to PVP deposits in the biopsies. In the most seriously affected patients, PVP deposition caused severe organ dysfunction and contributed to the fatal outcomes of two patients. All patients except for one were prescribed opioid substitution drugs (OSDs), and most of the patients admitted to having injected such medications. Several OSDs contain PVP. One methadone formulation that was marketed in Norway from 2007 to 2014 contained large amounts of very high MW PVP, making it the most likely source of PVP deposition. Although the presumed source of PVP in these patients has now been withdrawn from the market, pathologists should be aware of PVP deposits when evaluating biopsies from this patient group.publishedVersio

Polyvinylpyrrolidone deposition disease in patients with intravenous opioid use: a case series

The polymer polyvinylpyrrolidone (PVP) is an excipient widely used in prescription drugs. Depending on the molecular weight (MW), parenterally administered PVP may accumulate in various tissues. Consequently, moderate and high MW PVP have only been used in oral preparations since the late 1970s. Surprisingly, starting in 2009, pathology departments in Norway received biopsies revealing PVP deposition, all from patients with a history of intravenous drug use. We identified 13 patients with PVP deposition and re-evaluated 31 biopsies and two autopsies. Common indications for biopsy were renal insufficiency, anemia, pathological fractures, and abdominal complaints. We observed PVP deposits in all biopsies (kidney, hematopoietic bone marrow, bone, gastrointestinal tract, lymph node, and skin) and all sampled tissue from the autopsies. Overall, the clinical findings could be related to PVP deposits in the biopsies. In the most seriously affected patients, PVP deposition caused severe organ dysfunction and contributed to the fatal outcomes of two patients. All patients except for one were prescribed opioid substitution drugs (OSDs), and most of the patients admitted to having injected such medications. Several OSDs contain PVP. One methadone formulation that was marketed in Norway from 2007 to 2014 contained large amounts of very high MW PVP, making it the most likely source of PVP deposition. Although the presumed source of PVP in these patients has now been withdrawn from the market, pathologists should be aware of PVP deposits when evaluating biopsies from this patient group

Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: Report of a case with a fatal outcome

Background: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP–deposition caused by repeated injections of OSDs. Case presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues. Conclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup

Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome [version 2; peer review: 2 approved]

Background: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP–deposition caused by repeated injections of OSDs. Case presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues. Conclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup