The autosomal dominant acute hepatic porphyrias (AHPs), acute intermittent porphyria, hereditary coproporphyria (HCP) and variegate porphyria (VP), are low penetrance adult onset disorders caused by partial deficiency of enzymes of haem biosynthesis. All are associated with acute neurovisceral attacks, which are a consequence of the increased hepatic demand for haem triggered by hormones, stress, drugs or systemic infections which leads to upregulation of the pathway and overproduction of haem precursors 5-aminolaevulinic acid (ALA) and porphobilinogen (PBG). Acute episodes are characterised by severe abdominal pain, nausea, vomiting, hyponatraemia, hypertension and tachycardia, behavioural disturbance and can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if undiagnosed and untreated. VP and HCP may also present with photocutaneous skin lesions either alone or during acute symptoms. Diagnosis involves demonstrating increased excretion of PBG in urine. Treatment focuses on removing or managing triggers, supportive treatment and suppressing the hepatic haem pathway by administering human haemin. Chronic complications include hypertension, chronic kidney disease and hepatocellular carcinoma. A small proportion of symptomatic patients with AHP progress to repeated acute attacks which require preventative therapy. A new RNA interference therapy has recently been licensed and is likely to become the treatment of choice in this situation.

BACKGROUND:Porphyrias are a group of rare diseases leading to dysregulation in heme biosynthesis and the accumulation of heme precursors, including porphyrinogens, which in their oxidized states [porphyrins] are reddish or purple. Acute hepatic porphyrias (AHP) comprise four diseases that cause acute debilitating neurovisceral attacks. Despite diagnostic advances, AHP is often undiagnosed or misdiagnosed due to a lack of disease awareness, low clinical suspicion, variable presentation, and nonspecific symptoms that mimic more common diseases. Delays in diagnosis and treatment increase the risk of serious acute and chronic complications.METHODS:In order to assess whether symptoms alone or in combination might be utilized as important indicators or "purple flags" that, when present, should alert clinicians to suspect AHP and pursue specific diagnostic testing, we conducted a comprehensive review of the literature on AHP, including cohort studies and case reports over two epochs, from 1980 to 2006 and from 2012 to 2018.RESULTS:We found that severe abdominal pain, with or without acute central nervous system manifestations and peripheral neuropathy, continues to be the most frequent symptom. Hyponatremia, change in urine color, and certain chronic symptoms were also identified as features that should raise suspicion of AHP. To improve diagnosis of AHP, clinicians need to take a broad perspective, including demographic data and medical history, into consideration.CONCLUSIONS:The clinical features of AHP continue to be severe pain, especially pain in the abdomen. Other features that should raise suspicion are autonomic, peripheral, or central neuropathies, hyponatremia, and red-purple urine color.

A 27-year-old man with a background of schizophrenia presented during the summer months with a 2-day history of a blistering eruption predominantly affecting his hands, forearms and face. He had not knowingly been exposed to any chemicals or toxins and was otherwise well. Clinical examination revealed multiple, large, tense blisters affecting the sun-exposed sites. Histology subsequently demonstrated subepidermal blisters with minimal inflammation and negative immunofluorescence. Porphyrin biochemistry including faecal, urinary and serum samples were unremarkable and thus a diagnosis of pseudoporphyria was reached. There were no obvious triggers, however, olanzapine (an atypical antipsychotic) had been commenced 2 months previously and was deemed to be the most likely cause. This is the first report of pseudoporphyria being associated with an atypical antipsychotic and highlights the importance of eliciting an accurate drug history by specifically enquiring about any recent medication changes that could account for the clinical presentation.

Severe recurrent acute attacks of porphyria have traditionally been treated with either prophylactic human haemin or gonadorelin analogues (GnA) in females. Evidence on the most effective treatment for this patient subgroup is lacking. This audit surveyed the use of prophylactic GnA in the UK.Twenty female patients (who experienced between 2 and 45 acute attacks of porphyria requiring hospitalisation and treatment with human haemin prior to GnA prophylaxis) were included in the audit. Data was retrospectively collected based on patient history and case review.Twenty three treatment courses were given lasting a median period of 12 months. Monthly subcutaneous Goserelin was most commonly used. In three patients in whom timing with the menstrual cycle was not considered, an acute attack occurred after initiation of the first dose. The majority of patients experienced oestrogen deficiency symptoms during treatment. Fifty percent of the prescribed courses of GnA resulted in a degree of clinical benefit. This successfully treated group experienced between 3 and 20 acute attacks prior to and between 0 and 6 acute attacks during GnA treatment.The audit revealed large variation in practice in the United Kingdom regarding indication, duration of treatment, specific drug used and management of side effects. In view of the limited treatment options available for this cohort and the mixed outcome successes reported, we believe it is reasonable for porphyria specialists to continue offering GnA treatment to women with severe recurrent debilitating acute attacks of porphyria associated with the menstrual cycle, and we propose best practice guidelines to standardise management.

The porphyrias are disorders of haem biosynthesis which present with acute neurovisceral attacks or disorders of sun-exposed skin. Acute attacks occur mainly in adults and comprise severe abdominal pain, nausea, vomiting, autonomic disturbance, central nervous system involvement and peripheral motor neuropathy. Cutaneous porphyrias can be acute or chronic presenting at various ages. Timely diagnosis depends on clinical suspicion leading to referral of appropriate samples for screening by reliable biochemical methods. All samples should be protected from light. Investigation for an acute attack: • Porphobilinogen (PBG) quantitation in a random urine sample collected during symptoms. Urine concentration must be assessed by measuring creatinine, and a repeat requested if urine creatinine <2 mmol/L. • Urgent porphobilinogen testing should be available within 24 h of sample receipt at the local laboratory. Urine porphyrin excretion (TUP) should subsequently be measured on this urine. • Urine porphobilinogen should be measured using a validated quantitative ion-exchange resin-based method or LC-MS. • Increased urine porphobilinogen excretion requires confirmatory testing and clinical advice from the National Acute Porphyria Service. • Identification of individual acute porphyrias requires analysis of urine, plasma and faecal porphyrins. Investigation for cutaneous porphyria: • An EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy and random urine sample for TUP. • Whole blood for porphyrin analysis is essential to identify protoporphyria. • Faeces need only be collected, if first-line tests are positive or if clinical symptoms persist. Investigation for latent porphyria or family history: • Contact a specialist porphyria laboratory for advice. Clinical, family details are usually required.

The National Acute Porphyria Service (NAPS) provides acute care support and clinical advice for patients in England with active acute porphyria requiring haem arginate treatment and patients with recurrent acute attacks.This audit examined the benefits and complications of regular haem arginate treatment started with prophylactic intent to reduce the frequency of recurrent acute attacks in a group of patients managed through NAPS. We included 22 patients (21 female and 1 male) and returned information on diagnosis, indications for prophylactic infusions, frequency and dose, analgesia, activity and employment and complications including thromboembolic disease and iron overload.The median age at presentation with porphyria was 21 years (range 9-44), with acute abdominal pain as the predominant symptom. Patients had a median of 12 (1-400) attacks before starting prophylaxis and had received a median of 52 (0-1,350) doses of haem arginate. The median age at starting prophylaxis was 28 years (13-58) with a median delay of 4 years (0.5-37) between presentation and prophylaxis. The frequency of prophylactic haem arginate varied from 1 to 8 per month, and 67% patients were documented as having a reduction in pain frequency on prophylaxis. Only one patient developed clinically significant iron overload and required iron chelation, but the number of venous access devices required varied from 1 to 15, with each device lasting a median of 1.2 years before requiring replacement. Six patients stopped haem arginate and in three this was because their symptoms had improved. Prophylactic haem arginate appears to be beneficial in patients with recurrent acute porphyria symptoms, but maintaining central venous access may prove challenging.

The British and Irish Porphyria Network guidelines describe best practice in the clinical assessment, investigation and management of acute porphyria attacks and their complications, including severe attacks with neuropathy. Acute attacks of porphyria may occur in acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Aminolaevulinic acid dehydratase deficiency porphyria (ADP) is a very rare autosomal recessive porphyria; only six cases substantiated by mutation analysis have yet been described in the literature. Urinary porphobilinogen (PBG) is always raised in an acute attack due to AIP, VP or HCP and this analysis is essential to confirm the diagnosis. A positive result in a qualitative or semi-quantitative screening test must be followed by PBG quantitation at the earliest opportunity. However in a severely ill patient, treatment should not be delayed. Removal of precipitating factors, effective analgesia and control of symptoms with safe medication, attention to nutrition and fluid balance are essential. The indications for use of intravenous haem arginate are set out, together with advice on its administration. A small proportion of acute porphyria patients develop recurrent attacks and management options that may be considered include gonadotrophin-releasing hormone analogues, 'prophylactic' regular haem arginate infusion or ultimately, liver transplantation.

To the Editor: Acute intermittent porphyria (AIP)1 (MIM 176000) is a low-penetrance, autosomal dominant disorder caused by decreased activity of the third enzyme in the pathway of heme biosynthesis, hydroxymethylbilane synthase (HMBS). Partial deficiency of HMBS can lead to episodic life-threatening neurovisceral attacks of acute porphyria, which are often provoked by drugs, alcohol, or hormonal factors (1). Biochemical analyses of urinary porphobilinogen and porphyrins (fecal porphyrins and plasma porphyrins) can provide the diagnosis of AIP in symptomatic patients, but genetic testing for a defect in the HMBS gene (1) is required to accurately identify asymptomatic affected family members, who can then be counseled on the lifestyle modifications required to limit the risk of attacks. We previously reported on our experience with using direct genomic sequencing and dosage analysis of the HMBS gene for genetic analysis of AIP (2). We found a 98% sensitivity for detecting disease-causing mutations in unrelated symptomatic patients with a biochemical diagnosis of AIP (2), and we speculated that the cause in AIP patients in whom no mutation was found was likely to be mutations in unexplored parts of the gene, possible regulatory variants, or defects at another locus. We investigated a …

Hum Genet 1999;104:505–10. 4. Chretien S, Dubart A, Beaupain D, Raich N, Grandchamp B, Rosa J, et al. Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissuespecific or in housekeeping expression. Proc Natl Acad Sci U S A 1988;85:6–10. 5. Dir A, Buratti E. Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies. FEBS J 2010;227:841–55.

Acute neurovisceral attacks of porphyria can be life threatening. They are rare and notoriously difficult to diagnose clinically, but should be considered, particularly in female patients with unexplained abdominal pain, and associated neurological or psychiatric features or hyponatraemia. The diagnosis might be suggested by altered urine colour and can be confirmed by finding an elevated porphobilinogen concentration in fresh urine protected from light. Severe attacks require treatment with intravenous haem arginate and supportive management with safe drugs, including adequate analgesia. Intravenous glucose in water solutions are contraindicated as they aggravate hyponatraemia, which can prove fatal.

We present an interesting case of porphria cutanea tarda with hereditary haemochromatosis and non-classical congenital adrenal hyperplasia in a postmenopausal woman. This unusual combination of conditions does not appear to be reported in the literature. The exact mechanism causing porphyria in this patient is not clear. We consider the possibility that in addition to iron accumulation and excess alcohol, altered steroid milieu may have been a possible trigger for the development of bullous lesions in this patient.

This review critically appraises the data emerging from small retrospective and prospective cohort studies suggesting that patients with the autosomal dominant acute porphyrias may be at increased risk of hepatocellular cancer (HCC), hypertension (HT) and renal impairment. The most striking finding is a marked excess risk of HCC in Swedish patients with acute intermittent porphyria (AIP). As Sweden has a relatively high prevalence of AIP due to a founder effect, it is uncertain to what extent the finding is generalisable to other populations or other acute porphyrias and whether early intervention through screening can improve outcomes. As yet there is no evidence for the cost-effectiveness of systematic surveillance for HCC in acute porphyria outside Sweden. Data from several populations also suggest a high prevalence of chronic sustained HT and renal impairment in AIP, but it is uncertain if this represents a true excess risk, in particular for asymptomatic patients. As these long-term complications are important and potentially treatable, a pragmatic recommendation is that symptomatic patients with acute porphyria should be offered specialist long-term follow-up and, for those aged >50 years, annual liver ultrasound may be considered following discussion of the likely risks and benefits. Opportunistic cardiovascular risk assessment can readily be incorporated into a structured annual review so that appropriate drugs safe for use in acute porphyria are prescribed promptly. As these diseases are rare, collaborative international epidemiological studies such as those being coordinated through the European Porphyria Network are essential to inform best clinical practice.

Erythropoietic protoporphyria (EPP) is an inherited disorder that results from partial deficiency of ferrochelatase (FECH). It is characterized clinically by acute photosensitivity and, in 2% of patients, liver disease. Inheritance is usually autosomal dominant with low penetrance but is recessive in about 4% of families. A cross-sectional study of 223 patients with EPP in the United Kingdom identified six individuals with palmar keratoderma. We now show that these and three additional patients, from six families, have an inherited subtype of EPP which is characterized by seasonal palmar keratoderma, relatively low erythrocyte protoporphyrin concentrations, and recessive inheritance. No patient had evidence of liver dysfunction; four patients had neurological abnormalities. Patients were hetero- or homoallelic for nine different FECH mutations; four of which were previously unreported. Prokaryotic expression predicted that FECH activities were 2.7-25% (mean 10.6%) of normal. Neither mutation type nor FECH activity provided an explanation for the unusual phenotype. Our findings show that palmar keratoderma is a clinical indicator of recessive EPP, identify a phenotype that occurs in 38% of reported families with recessive EPP that to our knowledge is previously unreported, and suggest that patients with this phenotype may carry a lower risk of liver disease than other patients with recessive EPP.

Forensic psychiatrists are not as vulnerable to liability as general psychiatrists. The absence of a traditional physician-patient relationship and judicial and quasijudicial immunity are all protective against malpractice actions. Although the absence of a doctor-patient relationship removes an essential element of malpractice, other types of liability such as defamation and ordinary negligence are possible and may not be covered by malpractice insurance. A model is proposed for forensic psychiatry of a partial secondary doctor-patient relationship outweighed in most circumstances by duties to truth and/or the hiring attorney. Such a model seems most consistent with conflicting duties currently forced on all psychiatrists. This model has advantages of a duty, a violation of which is likely to be covered by malpractice insurance. Rather than deemphasizing partial secondary physician-patient responsibilities, it is advised to stress the important protection provided by judicial and quasijudicial immunity.

There are only four cases reported of acute intermittent porphyria (AIP) in association with porphyria cutanea tarda (PCT). Enzyme studies in these patients revealed a dual deficiency, with decreased activity of both porphobilinogen deaminase as seen in AIP and uroporphyrinogen decarboxylase, as seen in PCT. To date there have been no reports of treatment or follow up of these patients.A 48 year old lady was referred to Dermatology, in 1999 with a two week history of haemorrhagic blisters on the hands and feet after a holiday in Corfu. She had been diagnosed with AIP at the age of 17, having complained of abdominal pain and paraesthesia in the fingers and toes. The gene mutation causing this was subsequently identified by Professor Elder (University of Cardiff). She had had a hysterectomy at age 30 and had taken HRT since age 35. She had undergone bone marrow transplant aged 37 for acute myeloid leukaemia, and subsequently developed blisters on her feet and ears, which settled within a few weeks. She was taking Beta Blockers for hypertension. There was no family history of porphyria. Examination revealed tense non-haemorrhagic blisters on the dorsum of fingers, hands and toes. Investigations revealed elevated aminolaevulinic acid, porphobilinogen, uroporphyrin and 7-carboxyporphyrin with normal coproporphyrin. The results were consistent with a diagnosis of both porphyria cutanea tarda and acute intermittent porphyria. Plasma porphyrin screen was positive with a maximum emission at 618 nm. She has subsequently developed mild renal impairment and liver biopsy showed iron deposition.The HRT was stopped as estrogen can exacerbate both PCT and AIP, but she was unable to cope without it, because of menopausal symptoms. She was recommended oral supplements to aid weight gain and was subsequently treated unsuccessfully with hydroxychloroquine. She then underwent a course of bi-weekly venesection (total 11 units removed). This resulted in an improvement in symptoms and a marked decrease in ferritin and iron saturation levels.This case illustrates the complexity in managing patients with dual deficiency porphyrias, and reminds dermatologists of the long-term sequelae of these conditions. There are only four cases reported of acute intermittent porphyria (AIP) in association with porphyria cutanea tarda (PCT). Enzyme studies in these patients revealed a dual deficiency, with decreased activity of both porphobilinogen deaminase as seen in AIP and uroporphyrinogen decarboxylase, as seen in PCT. To date there have been no reports of treatment or follow up of these patients. A 48 year old lady was referred to Dermatology, in 1999 with a two week history of haemorrhagic blisters on the hands and feet after a holiday in Corfu. She had been diagnosed with AIP at the age of 17, having complained of abdominal pain and paraesthesia in the fingers and toes. The gene mutation causing this was subsequently identified by Professor Elder (University of Cardiff). She had had a hysterectomy at age 30 and had taken HRT since age 35. She had undergone bone marrow transplant aged 37 for acute myeloid leukaemia, and subsequently developed blisters on her feet and ears, which settled within a few weeks. She was taking Beta Blockers for hypertension. There was no family history of porphyria. Examination revealed tense non-haemorrhagic blisters on the dorsum of fingers, hands and toes. Investigations revealed elevated aminolaevulinic acid, porphobilinogen, uroporphyrin and 7-carboxyporphyrin with normal coproporphyrin. The results were consistent with a diagnosis of both porphyria cutanea tarda and acute intermittent porphyria. Plasma porphyrin screen was positive with a maximum emission at 618 nm. She has subsequently developed mild renal impairment and liver biopsy showed iron deposition. The HRT was stopped as estrogen can exacerbate both PCT and AIP, but she was unable to cope without it, because of menopausal symptoms. She was recommended oral supplements to aid weight gain and was subsequently treated unsuccessfully with hydroxychloroquine. She then underwent a course of bi-weekly venesection (total 11 units removed). This resulted in an improvement in symptoms and a marked decrease in ferritin and iron saturation levels. This case illustrates the complexity in managing patients with dual deficiency porphyrias, and reminds dermatologists of the long-term sequelae of these conditions.

We compared plasma phosphate concentrations in general practice patients and hospital inpatients and outpatients over an 8-month period. The distribution of results in all three groups was similar and 12–16% of results were at or below 0·8 mmol/L. In general practice patients, 8·3% of results from males and 12·1% from females were below the lower limit of their respective reference ranges. Eighteen of these patients (0·2% of results) had plasma phosphate concentrations ⩽ 0·4 mmol/L. On follow-up, only two of these patients had any attributable cause for their severe hypophosphataemia; in the remainder, it was unexpected and unexplained. Hypophosphataemia in outpatients and general practice patients is more common than has previously been appreciated. We present a strategy for further investigation of these patients.

Drug effects and poisoning must be considered when trying to identify the cause of bizarre or unexplained illness. Accurate, timely and confident identification of an unknown agent poses a challenge to the toxicology laboratory and may carry medico-legal implications. We describe a case of fatal poisoning, shown after death to be due to isoniazid, and discuss the approach to the problem of identifying this unexpected toxic agent.

One of 16 human small cell lung cancer cell lines examined was shown to synthesize a metabolite resembling 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. The NCI H82 line converted 25-hydroxyvitamin D3 (25OHD3) into a compound indistinguishable from 1,25-(OH)2D3 in 3 different high performance liquid chromatography systems. Electron impact mass spectra for the trimethylsilylethers of the metabolite and authentic 1,25-(OH)2D3 were indistinguishable. Binding to an anti-1,25-(OH)2D3 antibody was identical for the metabolite and authentic 1,25-(OH)2D3, whereas administration to rats in vivo caused equivalent stimulation of calcium transport measured in vitro in duodenal sacs. Activity of the H82 1 alpha-hydroxylase appears to be substrate dependent and is not stimulated by PTH, suggesting that it is similar to the enzyme expressed by activated macrophages and other cell types at extrarenal sites. Inhibition by ketoconazole indicates that, like the renal and extrarenal enzymes, the H82 enzyme is cytochrome P450 dependent. These data indicate that the H82 small cell lung cancer cell line constitutively expresses 25-hydroxyvitamin D3-1 alpha-hydroxylase and can synthesize 1,25-(OH)2D3.

In humans, proopiomelanocortin (POMC) and the peptides derived from it have been individually identified in plasma under differing conditions. However, direct quantitative comparison has proved difficult because of the limitations of RIAs. Using a panel of monoclonal antibodies recognizing different regions of POMC, we have developed specific two-site immunoradiometric assays (IRMAs) for the ACTH precursors (POMC and pro-ACTH), ACTH, beta-lipotropin (beta LPH), beta-endorphin (beta EP), and the N-terminal POMC fragment (N-POC). We have quantified these peptides directly in plasma from normal subjects under basal conditions and in response to different regulatory factors. Basal levels of ACTH precursors, 5-40 pmol/L, were greater than or equal to ACTH, less than 0.9-11.3 pmol/L; N-POC, 5.6-16.8 pmol/L; beta LPH, 2.5-6.7 pmol/L; and beta EP less than or equal to 1.7 pmol/L. ACTH, N-POC, beta LPH, and beta EP levels increased in parallel in response to metyrapone (n = 8) and decreased in response to dexamethasone (n = 8), whereas ACTH precursor concentrations did not respond. After human CRH administration, peripheral concentrations of ACTH, N-POC, and beta LPH showed similar increments (median increment, 163%, 145%, and 172%, respectively; n = 6). POMC peptide responses to human CRH were also assessed in inferior petrosal sinuses draining the pituitary in 20 patients with pituitary-dependent Cushing's disease. In these patients, the increment in ACTH after CRH exceeded that in ACTH precursors by 4-fold (median, 459% and 96%). An increase in the ratios of ACTH/N-POC and ACTH/beta LPH was also apparent after CRH stimulation. The increment in beta EP after CRH always exceeded the increments in POMC and beta LPH. In summary, these data suggest that significant concentrations of ACTH precursors are present in the circulation of normal subjects, that ACTH precursors are not regulated in the same way as the processed POMC peptides, and that ACTH and beta EP are preferentially released from the pituitary in response to CRH.

In the normal pituitary, glucocorticoids are the principal negative regulatory of the pro-opiomelanocortin (POMC) gene which gives rise to the biologically active peptides ACTH and beta-endorphin. In Cushing's syndrome, ACTH-secreting pituitary tumours show a degree of glucocorticoid resistance, whilst ACTH-secreting extra-pituitary tumours have an even greater resistance to glucocorticoid excess. In an attempt to understand the mechanism of this phenomenon, we have compared the effects of glucocorticoids on POMC mRNA and peptide secretion in human and mouse corticotroph adenoma cells and in small cell lung carcinoma (SCLC) cells. ACTH precursor peptides were inhibited within 24 h by 25-50 nM hydrocortisone in primary cultures from a human corticotroph adenoma. In the mouse corticotroph adenoma cell line (AtT20), inhibition of both ACTH precursors and ACTH was not observed after 24 h but, by 10 days, glucocorticoids suppressed peptide levels with a concentration causing 50% inhibition of 50 nM hydrocortisone and maximal inhibition at 500 nM hydrocortisone. In marked contrast, there was no response to 500 nM hydrocortisone in the five SCLC cell lines (COR L103, COR L42, COR L24, COR L31, DMS 79) all of which secrete ACTH precursors. However, two of the five SCLC cell lines (COR L31 and DMS 79) were responsive to 1000 nM hydrocortisone. POMC mRNA, quantitated by slot-blot analysis, gave similar results for the five SCLC cell lines, implying that the abnormality may occur at the level of gene expression. When one of the three resistant cell lines (COR L103) was incubated with 2000 nM hydrocortisone or 2000 nM dexamethasone a clear suppression of precursor peptides and POMC mRNA was observed.(ABSTRACT TRUNCATED AT 250 WORDS)