Cutaneous Porphyrias:Causes, symptoms, treatments and the Danish incidence 1989-2013

Porphyrias are rare diseases caused by altered haem synthesis leading to the accumulation of different haem intermediates. Neurovisceral attacks may occur in acute porphyrias, while photosensitivity is the presenting symptom in cutaneous porphyrias. We present here an overview of symptoms and a flowchart for the diagnosis of cutaneous porphyrias, with recommendations for monitoring and an update of treatment options. From the Danish Porphyria Register, we present the incidences and approximate prevalences of cutaneous porphyrias within the last 25 years. A total of 650 patients with porphyria cutanea tarda were identified, 73 with erythropoietic protoporphyria, 9 with variegate porphyria, 4 with hereditary coproporphyria and one with congenital erythropoietic porphyria. The total incidence of all porphyrias was ~0.52/100,000 per year.</p

A Clinical Study of the Cutaneous Manifestations of Chronic Renal Failure.

The kidney and the skin are the two large networks of the body with their abundant blood supply, far in excess of their nutritional demands, the former for the constancy of the milieu interior and the latter maintaining mainly homeostasis. No wonder therefore, that they share many diseases and reflect mutually one another’s pathology which should be made use of by the clinician. Scientific and technologic improvements during the second-half of the 20th century have provided renal replacement therapy as a life-sustaining option for many individuals who otherwise may have died. For each year of the last 10 years, the number of individuals with end stage renal disease has grown approximately 20,000 per year. Cutaneous examination of patients with end stage renal disease has shown that 50 – 100% of the patients have at least one dermatologic condition. In addition to end stage renal disease, Uremia and conditions associated with replacement therapy are fraught with numerous and, often relatively unique cutaneous disorders. AIMS : 1. To study the various cutaneous manifestations and their incidence in patients with chronic renal failure. 2. To study the age and sex incidence of the individual cutaneous manifestations. 3. To study the incidence and types of cutaneous infections in chronic renal failure. 4. To study the treatment-related (medical and dialysis) dermatologic manifestations of chronic renal failure. 5. To correlate between the skin manifestations of systemic disorders with chronic renal failure. CONCLUSION: This clinical study of cutaneous manifestations of chronic renal failure was done during the period December ’03 to December ‘05 revealed the following 1. Most of the specific cutaneous manifestations of chronic renal failure were seen in this study. Pruritus and xerosis were the most common among the specific cutaneous manifestations of chronic renal failure. Pigmentary alterations and nail abnormalities were the next. Mucosal and hair abnormalities were noted in good percentage of cases. Nearly 10% had perforating dermatosis and purpura. Interesting findings noted in this study were digital gangrene, poor wound healing, and restless leg syndrome. 2. Skin changes due to treatment reported were arteriovenous shunt dermatitis, keratotic pits of palms in small percentage and blue nails in a patient during hemodialysis, other than pruritus and pigmentary alterations. 3. Cutaneous infections and infestations were seen in 43.8 % of the cases. This high incidence could be due to impaired immunity resulting in increased susceptibility to infections in chronic renal failure patients. Fungal infections were the most common, followed by viral, bacterial and parasitic infestations. 4. Associated skin changes of systemic diseases helped in finding varying etiologies of chronic renal failure such s diabetes mellitus, systemic lupus erythematosus, scleroderma, vasculitis, Henoch schonlein purpura, idiopathic thrombocytopenic purpura. A case of cortical medullary disease in Ellis van creveld syndrome was reported with cutaneous changes. A case of tuberous sclerosis with renal involvement and skin changes was seen. Other associated skin changes were not related to the etiology and were found to be just coincidental

Investigation and management of a raised serum ferritin

Serum ferritin level is one of the most commonly requested investigations in both primary and secondary care. Whilst low serum ferritin levels invariably indicate reduced iron stores, raised serum ferritin levels can be due to multiple different aetiologies, including iron overload, inflammation, liver or renal disease, malignancy, and the recently described metabolic syndrome. A key test in the further investigation of an unexpected raised serum ferritin is the serum transferrin saturation. This guideline reviews the investigation and management of a raised serum ferritin level. The investigation and management of genetic haemochromatosis is not dealt with however and is the subject of a separate guideline

Ihoporfyriat : kliininen ja histopatologinen tutkimus

The prevalence of variegate porphyria (VP) (2.1:100 000, in 2006 n=108) was higher in Finland than elsewhere in European countries due to a founder effect (R152C). The incidence of VP was estimated at 0.2:1 000 000 based on the number of new symptomatic patients yearly. The prevalence of porphyria cutanea tarda (PCT) was 1.2:100 000 (in 2006 n=63), which is only one fourth of the numbers reported from other European countries. The estimated incidence of PCT was 0.5:1 000 000. Based on measurements of the uroporphyrinogen decarboxylase activity in erythrocytes, the proportion of familial PCT was 49% of the cases. The prevalence of erythropoietic protoporphyria (EPP) was at 0.8:100 000 (in 2006 n=39) including asymptomatic carriers of a mutation in the ferrochelatase (FECH) gene. The incidence of EPP was estimated at 0.1:1 000 000. After 1980 the penetrance was 37% among patients with VP. Of the mutation carriers (n=57) 30% manifested with skin symptoms. Frequency of skin symptom as only clinical sign was stable before or after 1980 (22% vs. 21%), but acute attacks became infrequent (29% vs. 7%). Of the symptomatic patients 30% had both acute attacks and skin symptoms and 80% had skin symptoms. Fragility (95%) and blistering (46%) of the skin in the backs of the hands were the most common skin symptoms. Transient correction of porphyrin metabolism using eight haem arginate infusions within five weeks had no effect on the skin symptoms in three of four patients with VP. In one case skin symptoms disappeared transiently. One patient with homozygous VP had severe photosensitivity since birth. Sensory polyneuropathy, glaucoma and renal failure developed during the 25-year follow-up without the presence of acute attacks. The I12T mutation was detected in both of his alleles in the protoporphyrinogen oxidase gene. Lack of skin symptoms and infrequency of acute attacks (1/9) in the patients with I12T mutation at the heterozygous stage indicate a mild phenotype (the penetrance 11%). Four mutations (751delGAGAA, 1122delT, C286T, C343T) in the FECH gene were characterised in four of 15 families with EPP. Burning pain (96%) and swelling (92%) of the sun-exposed skin were the major skin symptoms. Hepatopathy appeared in one of 25 symptomatic patients (4%). Clinical manifestations and associated factors of PCT were similar in the sporadic and familial types of PCT. The majority of the patients with PCT had one to three precipitating factors: alcohol intake (78%), mutations in hemochromatosis associated gene (50%), use of oestrogen (25% of women) and hepatitis B or C infections (25 %). Fatty liver disease (67%) and siderosis (67%) were commonly found in their liver biopsies. The major histopathological change of the sun-exposed skin in the patients with VP (n=20), EPP (n=8) and PCT (n=5) was thickening of the vessel walls of the upper dermis suggesting that the vessel wall is the primary site of the phototoxic reaction in each type of porphyria. The fine structure of the vessel walls was similar in VP, EPP and PCT consisting of the multilayered basement membrane and excess of finely granular substance between the layers which were surrounded by the band of homogenous material. EPP was characterised by amorphous perivascular deposits extending also to the extravascular space. In direct immunofluorescence study homogenous IgG deposits in the vessel walls of the upper dermis of the sun-exposed skin were demonstrated in each type of porphyria. In EPP the excess material around vessel walls consisted of other proteins such as serum amyloid protein, and kappa and lambda light chains in addition to the basement membrane constituents such as collagen IV and laminin. These results suggest that the alterations of the vessel walls are a consequence of the repeated damage and the repairing process in the vessel wall. The microscopic alterations could be demonstrated even in the normal looking but sun-exposed skin of the patients with EPP during the symptom-free phase suggesting that vascular change can be chronic. The stability of vascular changes in the patients with PCT after treatment indicates that circulating porphyrins are not important for the maintenance of the changes.Porfyriat ovat perinnöllisiä aineenvaihduntasairauksia, jotka aiheutuvat hemin biosynteesin entsyymien häiriöstä. Tämä johtaa porfyriinien liikatuotantoon maksassa tai luuytimessä. Porfyriineillä on kyky reagoida valoenergian kanssa, jonka johdosta ne aiheuttavat potilaille valoherkkyyttä. Väitöskirjatyössä selvitettiin iho-oireisten porfyrioiden, porphyria variegatan (PV), porphyria cutanea tardan (PCT) ja erytropoieettisen protoporfyrian (EPP) esiintymistä Suomessa ennen 1980 ja 1980-2006 välisenä aikana. PV:n esiintyvyys oli 2.1:100 000 (108 potilasta), mikä on korkeampi kuin muissa Euroopan maissa. PV:n sairastavuus oli 0.2:1 000 000. PCT:n esiintyvyys oli 1.2:100 000 (63 potilasta), mikä on huomattavasti alhaisempi kuin muualla Euroopassa. PCT:n sairastavuus oli 0.5:1 000 000. Punasolujen uroporfyrinogeenidekarboksylaasin aktivisuus todettiin alentuneeksi 49 %:lla potilaista, mikä viittaa suvussa esiintyvään tautimuodon (tyyppi II PCT) olevan oletettua tavallisemman. EPP:n esiintyvyys oli 0.8:100 000 (39 potilasta) ja sairastavuus 0.1:1 000 000. EPP-potilaita löytyi 15:sta eri suvusta. Vuoden 1980 jälkeen todetuista yli 14 vuotiaista PV-potilaista (57), joilla oli löytynyt mutaatio, 30 %:lla esiintyi iho-oireita ja kaikkiaan 37 %:lla esiintyi akuutteja porfyriakohtauksia ja/tai iho-oireita. Kun vertailtiin oireiden esiintymistä ennen vuotta 1980 ja sen jälkeen diagnosoiduilla potilailla, akuuttien kohtausten tiheys oli vähentynyt oleellisesti (51 %:vs 18 % potilaista), kun taas iho-oireiden esiintyminen oli lähes ennallaan (44 % vs 30 % potilaista). Lähes kaikilla oireisilla potilailla (80 %) esiintyi iho-oireita. Valoherkkyys ilmeni yleisimmin kädenselkien ihon haaavautumisalttiutena (95 % potilaista) ja rakkulointina (46 % potilaista). Koska PV:n iho-oireisiin ei ole hoitoa tarjolla, tutkimme toistuvien hemiarginaatti-infuusioiden tehoa viiden viikon aikana neljällä iho-oireisella potilaalla. Hoito korjasi tilapäisesti porfyriiniaineenvaihdunnan häiriön kaikilla potilailla, mutta iho-oireet hävisivät ainoastaan yhdellä potilaalla. Väitöskirjatyössä löydettiin neljä ferrokelataasigeenin mutaatiota (751delGAGAA, 1122delT, C286T, C343T) neljässä eri EPP-suvussa. Yleisimmät iho-oireet 25:lla valoherkkyydestä kärsivällä potilaalla olivat ihon polttelu (96 % potilaista) ja turvotus (92 % potilaista) heti auringolle altistumisen jälkeen. Yhdelle potilaalle kehittyi maksavaurio taudin komplikaationa. PCT:ssä iho-oireet sekä taudille altistavat tekijät olivat samanlaisia hankitussa (tyyppi I) ja periytyvässä (tyyppi II) tautimuodoissa. Yleisimmät altistavat tekijä olivat alkoholin käyttö (78%) ja hemokromatoosigeenin mutaatiot (50%). Hieman harvinaisempia altistavia tekijöitä olivat hepatiitti B tai C infektio (25 %) sekä naisilla estrogeenivalmisteiden käyttö (25%). Maksan toiminta kuvaavat transaminaasi-arvot olivat koholla 80 %:lla potilaista. Maksabiopsiassa, joka oli tehty 21 potilaalle, yleisin löydös oli maksan rasvoittuminen (67%) sekä sideroosi (67%). PCT:n iho-oireet olivat samanlasia kuin PV:ssä, jonka johdosta oikea diagnoosin määritys plasman, virtsan ja ulosteen porfyriinien mittauksella on tärkeä. Valolle altistuneen ihon histopatologisessa tutkimuksessa keskeisin löydös kaikissa ihoporfyrioissa oli ylädermiksen verisuonten seinämän paksuuntuminen, joka tuli parhaiten esiin PAS-värjäyksessä. Elektronimikroskooppisessa tutkimuksessa todettiin verisuonten seinämissä monikerroksinen tyvikalvo ja homogeenisen materiaalin kertyminen seinämän ympärille. EPP:ssä havaittiin huomattavia ylimääräisen materiaalin kertymiä myös verisuonten seinämän ulkopuolella. Näissä kertymissä sekä verisuonten seinämissä osoitettiin osoitettiin verenkierrosta peräisin olevien proteiinien sekä tyvikalvon rakenneaineiden kasautumista. Immunofluoresenssitutkimuksessa todettiin IgG:n kertyminen verisuonten seinämään kaikissa ihoporfyrioissa. Löydökset viittaavat siihen, että verisuonen seinämä on ensisijainen vauriokohta ihon valoreaktiossa. Havaitut muutokset kehittyvät todennäköisesti toistuvien seinämävaurioiden seurauksena. Ihon mikroskooppiset muutokset olivat osoitettavissa EPP:ssä myös oireettomana kautena ja PCT:ssä muutokset säilyivät myös sen jälkeen kun tauti oli hoidettu remissioon. Tulokset viittaavat siihen että ihon mikroskooppiset muutokset ovat kroonisia. Todetut histopatologiset muutokset eivät ole spesifisiä porfyrialle, jonka johdosta porfyriadiagnoosin tulee aina perustua veren, virtsan ja ulosteen porfyriinimittauksiin

Hyperferritinemia—a clinical overview

Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors’ own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed.publishedVersio

Impacts of Black Box Warning, National Coverage Determination, and Risk Evaluation and Mitigation Strategies on the Inpatient On-Label and Off-label Use of Erythropoiesis-Stimulating Agents

Background: FDA black box warning, Risk Evaluation and Mitigation Strategies (REMS), and CMS national coverage determination (NCD) aim to reduce inappropriate use of erythropoiesis-stimulating agents (ESAs) that are widely used in anemic patients. Previous studies have not linked specific safety interventions to changes in ESA utilization patterns in the inpatient settings nor assessed such interventions on off-label use of the drugs. Ineffectiveness of the intervention and lag time between such interventions and the observed change in clinical practice could lead to serious clinical outcomes. In addition, such interventions may unintentionally reduce on-label and some off-label use of ESAs considered “appropriate” in patients who could otherwise benefit. Objectives: The primary aim of the study is to quantify the impacts of the (1) addition of black box warning, (2) implementation of NCD, and (3) institution of REMS on ESA on-label and off-label utilization patterns of adult inpatients. Demographic, clinical condition, physician, and hospital characteristics of ESAs users by their use category are also described in detail. Methods: Electronic health records in Cerner Database from January 1, 2005 to June 30, 2011 were used. The use of the two erythropoietic drugs: epoetin alfa and darbepoetin alfa were categorized into three groups using ICD-9-CM diagnoses and procedures codes and patients’ medication information. The three categories were (1) on-label use (approved by the FDA); (2) off-label use supported (use for the indications not approved by the FDA, but there is strong clinical evidence to support its use); and (3) off-label use unsupported (use for the indications not approved by the FDA and lacking clinical evidence). The immediate and trend impacts of the interventions on the proportion of ESAs prescribed for each usage category between 2005 and 2011 were assessed using an interrupted time series technique. The likelihood of receiving ESAs among patients with on-label, off-label supported, off-label unsupported indications was assessed using a generalized estimating equation approach with binary logistic regression technique, clustering for hospitals and controlling for potential confounders such as patient characteristics, patient clinical conditions, physician specialty, and hospital characteristics. Results: During the study period, there were 111,363 encounters of ESA use. These encounters represented 86,763 patients admitted to Cerner health system between January 1, 2005 and June 30, 2011. Of these patients, 66,121 were prescribed epoetin alfa only (76.2%); 20,088 darbepoetin alfa only (23.2%); and 554 were prescribed both epoetin alfa and darbepoetin alfa (0.6%). Forty-nine percent of the patients used ESAs for the on-label indications, 8.6% for off-label supported indications, and 42.7% for the off-label unsupported indications. The main uses of ESAs in our sample were for CKD (ONS, 41.1%) and chronic anemia (OFU, 31.8%). From 2005 to 2010, the proportion of visits with ESA ONS and OFS use decreased 53.2% and 81.9%, while ESA OFU increased 112.6%. Results from binary logistic regression using GEE model showed overall decreasing trends in ESA use for the on-label and off-label supported indications, but not off-label unsupported indications. REMS had no impact on the odds of receiving ESAs among patients with on-label and off-label conditions. Black box warning reduced the odds of being prescribed with epoetin alfa in patients with off-label unsupported conditions by 40%. It was also associated with 4% and 15% per month reduction in the odds of using darbepoetin alfa in patients with off-label supported and unsupported conditions. Lastly, there was a significant decline in all categories of ESA use the month after Medicare national coverage determination was implemented. The impact of NCD ranged from a 20% reduction in the odds of off-label supported use to a 37% reduction in on-label use. Age, gender, race, source of payment, admission type, clinical complexity, discharge disposition, and hospital size were significant associated with ESA use on-label and off-label. Conclusion: This study was the first to determine the impact of safety interventions on ESA on-label and off-label utilization patterns in the inpatient settings using the Cerner database. We demonstrated lag between the interventions and observed change in clinical practice, and the relative impacts of three types of safety interventions on on-label and off-label ESA use in the hospital settings. The indirect impact of the reimbursement change was the potential unintended consequence of reducing the likelihood of receiving ESAs for a patient with indicated conditions who could have otherwise benefited from the drugs

Erythropoietic protoporphyrias:Pathogenesis, diagnosis and management

The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.</p

Pseudoporfiria humana y experimental

Si bien las pseudoporfirias no son enfermedades metabólicas presentanalteraciones en el metabolismo del hemo. La pseudoporfiria en hemodiálisis se caracteriza por una falla parcial enla actividad del ALA-D en sangre de pacientes hemodializados al igual que enla Nueva Porfiria Aguda y las adquiridas por plomo, alcohol o en los casos detirosinemia. Como consecuencia de ello se acumula ALA. La hemodiálisisrecupera parcialmente estos parámetros bioquímicos, aunque no los lleva a lanormalidad. A su vez, el ALA-D es una enzima oligomérica, y de sus 8 subunidadessólo 2 constituyen el dímero funcional, donde el zinc y los grupos sulfhidrilosjuegan un papel importante en el mantenimiento del mismo. En base al conocimiento sobre las alteraciones del camino metabólicodel hemo y sus metabolitos nos interesó llevar a cabo un estudio completo ensangre de pacientes hemodializados pseudoporfiricos, antes y después deltratamiento de diálisis, con el objetivo de establecer los parámetros bioquímicosen la pseudoporfiria en pacientes hemodializados y en el modelo experimentalde Pseudoporfiria por acido nalidíxico. Debe enfatizarse que si bien se realizaron los estudios en pacienteshemodializados, los mismos se extendieron a pacientes con transplante renalreciente, llevándose a cabo el estudio de las enzimas y los niveles demetabolitos como glutatión y zinc, que pueden estar asociados a alteracionesmetabólicas. Se ha estudiado además, la estructura y cinética de inhibicion del ALA-Dde GR de un factor plasmático presente en plasma de pacienteshemodializados y con transplante renal.Fil: Guolo, Marcelo Nestor. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Investigation of an atypical protoporphyric family in South Africa

Includes bibliographical references (leaves 171-184).Affected members of the family investigated in this dissertation presented with photosensitivity and raised red cell protoporphyrin concentrations, indicative of protoporphyria. Further examination of this family revealed features that were atypical of erythropoietic protoporphyria. These included a highly penetrant disease, disease severity as expressed by more prevalent hepatic complications, a preponderance of protoporphyrin in its zinc chelated form, a therapeutic response to iron supplementation, and an absence of mutations in the ferrochelatase gene or haplotype markers associated with erythropoietic protoporphyria. We have reviewed clinical data from this family, established a ferrochelatase enzyme assay in our laboratory, and shown normal ferrochelatase enzyme activity in affected subjects