Role of two nutritional hepatic markers (insulin‐like growth factor 1 and transthyretin) in the clinical assessment and follow‐up of acute intermittent porphyria patients

Objective. Acute intermittent porphyria (AIP) is caused by a deficiency of hydroxymethylbilane synthase. Clinical manifestations are abdominal pain and neurovisceral symptoms, accompanied by overproduction of heme‐precursors in the liver, which frequently remains long‐lasting in AIP patients. We tested the hypothesis that this condition may be associated with alterations of hepatic proteins known to be either increased or decreased in serum according to diverse pathological conditions including malnutrition, inflammation or liver disease. Design. Serum proteins were analyzed in 26 biochemically active AIP patients that were classified according to the EPI (European Porphyria Initiative) guidelines as follows: (i) patients who presented a single acute attack having remained so far free of clinical symptoms; (ii) patients who present recurrent attacks or chronic symptoms associated with exacerbations of AIP. Results. Most of the serum proteins were within normal limits, however insulin‐like growth factor 1 (IGF‐1) was decreased in 53.8% of AIP patients (z‐score = ?2.86 ± 0.37) and transthyretin (prealbumin) was found significantly decreased in 38.5% of them. The IGF‐1 z‐score was lower in group B versus group A patients (?2.66 vs. ?1.43; P = 0.024). The coincident decrease of both IGF‐1 and transthyretin was associated with worsening of the clinical condition. Conclusions. This first study in humans suggests that the clinical expression AIP is associated with a state of under‐nutrition and/or with hepatic inflammation due to the sustained accumulation of heme‐precursors. We propose the use of both IGF‐1 and transthyretin as biomarkers of disease morbidity/severity for the clinical follow‐up of AIP patients.     

Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria

OBJECTIVE: To assess signs of distal neuropathy in patients with acute intermittent porphyria (AIP). DESIGN: A population-based study. SUBJECTS: All patients with DNA-verified AIP >/= 18 years of age in the four most northerly counties of Sweden. INTERVENTION: Validated neuropathic signs and tests such as monofilament test, neuropathic pain, dry feet, extensor digitorum brevis (EDB) test, loss of forefoot arch, hammer toes and ulceration. RESULTS: A total of 356 patients were registered and 339 of them (95%) participated in the neuropathy study. The chronic neurological signs were symmetrical and similar to those in type 1 diabetic patients. Significant impairment was found concerning perception, EDB test, lower leg pain, ankle and knee tendon reflexes, but not concerning dry feet, loss of forefoot arch and hammer toes, on comparing patients with manifest versus latent AIP. The neurological signs were more severe in the diabetic patients (n = 298). Five AIP patients had permanent quadriplegia after severe attacks. CONCLUSIONS: Patients with manifest AIP had significantly more signs of distal chronic, symmetrical neuropathy of axonal type than did patients with latent AIP. More grave neurological lesions appear to develop after severe attacks.     

Variegate porphyria in a 46‐year‐old patient taking sibutramine for weight loss

The acute hepatic porphyrias can cause life‐threatening attacks of neurovisceral symptoms that mimic other acute medical conditions. Variegate porphyria caused by mutations in the protoporphyrinogen oxidase (PPOX) gene is a latent disorder characterized by exacerbations induced by fasting, alcohol consumption or certain drugs. We describe the case of a 46‐year‐old female patient presenting with a first episode of symptomatic porphyria after 10 d of sibutramine treatment for weight loss. Genetic analysis showed a heterozygous R168H hot spot mutation in the PPOX gene. A putative effect of sibutramine on the hepatic haem biosynthetic pathway and reduced food intake have likely caused this exacerbation of a porphyria attack. Although this may be the first case report of this kind, the risk of acute porphyria should be considered in patients using pharmacotherapy for obesity.     

The Therapeutic Potential of Candoxatril,a Neutral Endopeptidase Inhibitor,in Humans

Candoxatril (UK‐79,300) is the orally active prodrug of candoxatrilat (UK‐73,967), the active enantiomer of (±) candoxatrilat (UK‐69,578), a potent neutral endopeptidase inhibitor. This article describes the rationale behind the use of this drug in the treatment of hypertension and chronic heart failure in humans. It further describes the pharmacokinetic and pharmacodynamics of candoxatril in preclinical animal studies, normal healthy individuals, and in patients with hypertension and chronic cardiac failure. In addition, we have described the initial results of clinical trials in hypertension and chronic cardiac failure, together with the potential future clinical developments of combined neutral endopeptidase/angiotensin converting enzyme inhibitors.     

Pain Management Programmes for Non‐English‐Speaking Black and Minority Ethnic Groups With Long‐Term or Chronic Pain

Increasing ethnic diversity in the UK means that there is a growing need for National Health Service care to be delivered to non‐English‐speaking patients. The aims of the present systematic review were to: (1) better understand the outcomes of chronic pain management programmes (PMPs) for ethnic minority and non‐English‐speaking patients and (2) explore the perspectives on and experiences of chronic pain for these groups. A systematic review identified 26 papers meeting the inclusion criteria; no papers reported on the outcomes of PMPs delivered in the UK. Of the papers obtained, four reported on PMPs conducted outside the UK; eight reported on ethnic differences in patients seeking support from pain management services in America; and the remaining papers included literature reviews, an experimental pain study, a collaborative enquiry, and a survey of patient and clinician ratings of pain. The findings indicate a lack of research into UK‐based pain management for ethnic minorities and non‐English‐speaking patients. The literature suggests that effective PMPs must be tailored to meet cultural experiences of pain and beliefs about pain management. There is a need for further research to explore these cultural beliefs in non‐English‐speaking groups in the UK. Culturally sensitive evaluations of interpreted PMPs with long‐term follow‐up are needed to assess the effectiveness of current provision. Copyright © 2015 John Wiley & Sons, Ltd.     

The Management of Acute Pulmonary Arterial Hypertension

Acute pulmonary arterial hypertension (PAH), which may complicate the course of many complex disorders, is always underdiagnosed and its treatment frequently begins only after serious complications have developed. Acute PAH is distinctive because they differ in their clinical presentation, diagnostic findings, and response to treatment from chronic PAH. The acute PAH may take either the form of acute onset of chronic PAH or acute PAH or surgery‐related PAH. Significant pathophysiologic differences existed between acute and chronic PAH. Therapy of acute PAH should generally be aimed at acutely relieving right ventricular (RV) pressure overload and preventing RV dysfunction. There are three classes of drugs targeting the correction of abnormalities in endothelial dysfunction, which have been approved recently for the treatment of PAH: (1) prostanoids; (2) endothelin receptor antagonists; and (3) phosphodiesterase‐5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH. Intravenous epoprostenol is suggested to serve as the first‐line treatment for the most severe patients. In the other situations, the first‐line therapy may include bosentan, sildenafil, or a prostacyclin analogue. Recent advances in the management of PAH have markedly improved prognosis.     

Could attacks of abdominal pain in cases of acute intermittent porphyria be due to intestinal angina?

Abdominal pain is by far the most serious symptom in attacks of acute intermittent porphyria. Its cause is unknown. This case study suggests visceral ischaemia as a possible cause of the abdominal pain. A 31-year-old woman with recurrent bouts died during an attack; the autopsy revealed a 20-cm necrotic gangrene in the ileum. A protracted intestinal vasospasm could have been the immediate cause of death. It is discussed whether intestinal angina could be the cause of the abdominal pain in acute intermittent porphyria.     

Atypical attack of acute intermittent porphyria--paresis but no abdominal pain

We report a case of acute intermittent porphyria (AIP) in a 45-year-old woman. Her first attack occurred at the age of 38. Because of escalating cyclical premenstrual attacks, the following 2 years, depletion of the endogenous sex hormone was considered as haeme arginate treatment proved insufficient. Gonadotropin releasing hormone agonist treatment with low-dose oestradiol add back was quite successful initially but was abandoned after 18 months when progesterone add back precipitated a severe attack. Following hysterectomy and oophorectomy at age 42 and oestradiol add back, a remarkable monthly regularity of attacks ensured periodically but with milder symptoms. Two years after surgery, preceded by six attack-free months, a puzzling symptom-shift occurred, from abdominal pain, back and thigh pain during the attacks, to solely severe distal extensor paresis in the arms. Haeme arginate treatment interrupted the progress of the paresis almost immediately and motor function improved considerably up to the 9-month follow-up. Electrophysiological examination revealed only motor neuropathy, consistent with axonal degeneration. Subsequently the symptoms changed yet again, to sensory disturbances with numbness and dysesthesia as the primary expression followed by rather mild abdominal pain. However, cyclical attacks occurred, despite absence of endogenous ovarial hormone production, possibly attributable to impaired oestrogen metabolism in the liver, or adrenal oestrogen production. Treatment comprising oophorectomy, low-dose oestradiol add back and haeme arginate infusion for 2 days on the appearance of early AIP symptoms is now quite successful affording improvement in life quality.     

Acute intermittent porphyria in women: clinical expression,use and experience of exogenous sex hormones. A population-based study in northern Sweden

OBJECTIVE: To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP. DESIGN: A retrospective population-based study. SUBJECTS: All women aged > or =18 years (n = 190) with DNA-diagnosed AIP in northern Sweden. RESULTS: A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty-two women (25%) aged > or =45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged > or =45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014). CONCLUSIONS: About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.     

Acute intermittent porphyria and chronic transaminase elevation

Acute intermittent porphyria is an autosomal dominant inherited disorder resulting from a deficiency of porphobilinogen deaminase activity, the third enzyme in the heme biosynthesis pathway. This disease is uncommon, although the prevalence is higher in asymptomatic heterozygotic carriers; however, this prevalence is difficult to establish because of the absence of symptoms. Although acute intermittent porphyria is a multisystemic disease, its most common form of presentation is abdominal pain and neurological or mental symptoms, which can sometimes be due to precipitating factors such as reduced energy intake, smoking, alcohol, some drugs, and stress. Diagnosis can be made by testing urinary porphobilinogen levels, with subsequent measurement of enzyme activity and DNA testing. Treatment is based on prevention of porphyria attacks by avoiding precipitating factors and early administration of intravenous glucose or hemin therapy. We present the case of a patient diagnosed with acute intermittent porphyria based on study of chronic mild alanine aminotransferase (ALT) elevation.     

Clinical features of gout

Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals in the joints and soft tissues, consisting of a self-limited acute phase characterized by recurrent attacks of synovitis and a chronic phase in which inflammatory and structural changes of the joints and periarticular tissues may lead to persistent symptoms. Acute gout is characterized by a sudden monoarthritis of rapid onset, with intense pain, mostly affecting the big toe (50% of initial attacks), the foot, ankle, midtarsal, knee, wrist, finger, and elbow. Acute flares also occur in periarticular structures, including bursae and tendons. The presence of characteristic MSU crystals in the joint fluid, appearing needle-like and showing strong negative birefringence by polarized microscopy, is pivotal to confirm the diagnosis of gout. The time interval separating the first attack from subsequent episodes of acute synovitis may be widely variable, ranging from a few days to several years. During the period between acute attacks the patient is asymptomatic even if MSU deposition may continue to increase silently. The factors that control the rate, location, and degree of ongoing deposition in gouty patients are not well defined. Chronic gout is the natural evolution of untreated hyperuricemia in patients with gouty attacks followed by pain-free intercritical periods. It is characterized by the deposition of solid MSU crystal aggregates in a variety of tissues including joints, bursae and tendons. Tophi can occur in a variety of locations including the helix of the ear, olecranon bursa, and over the interphalangeal joints. Their development is usually related with both the degree and the duration of hyperuricemia. About 20% of patients with gout have urinary tract stones and can develop an interstitial urate nephropathy. There is a strong association between hyperuricaemia and the metabolic syndrome (the constellation of insulin resistance, hypertension, obesity and dyslipidaemia), and gouty patients often have a medical history of kidney disease, diabetes mellitus and signs of vascular illness such as coronary artery disease, heart failure and stroke, resulting with a poor overall quality of life.     

Subclinical acute intermittent porphyria. An uncommon cause of chronic hepatitis

Acute porphyria is a term that encompasses a group of hereditary disorders involving defects in heme metabolism, characterized by acute episodes of abdominal pain, acute hypertension, tachycardia and neuropsychiatric disorders, sometimes leading to convulsions, ascending paralysis and coma. Misdiagnosis or delayed diagnosis can seriously worsen prognosis. We report the case of a woman with subclinical acute intermittent porphyria and chronic hepatitis incidentally diagnosed due to transaminase elevation on laboratory analysis.     

Mechanisms linking obesity to hypertension

Obesity‐related hypertension is increasingly recognized as a distinct hypertensive phenotype requiring a modified approach to diagnosis and management. In this review rapidly evolving insights into the complex and interdependent mechanisms linking obesity to hypertension are discussed. Overweight and obesity are associated with adipose tissue dysfunction, characterized by enlarged hypertrophied adipocytes, increased infiltration by macrophages and marked changes in secretion of adipokines and free fatty acids. This results in chronic vascular inflammation, oxidative stress, activation of the renin‐angiotensin‐aldosterone system and sympathetic overdrive, eventually leading to hypertension. These mechanisms may provide novel targets for anti‐hypertensive drug treatment. Recognition of obesity‐related hypertension as a distinct diagnosis enables tailored therapy in clinical practice. This includes lifestyle modification and accommodated choice of blood pressure‐lowering drugs.     

Rationale for calcium entry-blocking drugs in systemic hypertension complicated by coronary artery disease

There is considerable rationale for the use of the calcium entry-blocking drugs for the treatment of hypertension and prevention of recurrent episodes of angina pectoris in patients with systemic hypertension and significant coronary artery disease--the 2 entities commonly occurring together. Calcium entry-blocking drugs improve myocardial blood flow while decreasing myocardial oxygen demand. These agents can be given to most patients with ischemic heart disease and its complications, and are associated with a relatively low incidence of serious adverse effects and toxicity during long-term therapy. They reduce the frequency of anginal attacks, prolong exercise time to ST-segment depression or angina and improve exercise capacity. With long-term therapy, tolerance does not develop as it does in many patients with the "long-acting" nitrates. Calcium entry-blocking drugs reduce systolic blood pressure in patients with hypertension by a decrease in peripheral vascular resistance and a uniform improvement in blood flow affecting the myocardium, kidney and brain. There are no central nervous system adverse effects and hypokalemia does not occur. Unlike therapy with the beta-blocking drugs, chronic treatment with the calcium entry blockers does not reduce the serum level of high-density lipoprotein cholesterol nor increase serum triglyceride concentration. The calcium blockers decrease the arterial blood pressure without increasing intravascular plasma volume and are associated with only a slight increase in reflex-mediated sympathetic activity and heart rate, the latter occurring predominantly with nifedipine. Calcium entry-blocking drugs provide alternative or preferred therapy to beta-blocking agents in patients with a combination of hypertension and angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association of accelerated switch from vertebral end‐plate Modic I to Modic 0 signal changes with clinical benefit of intradiscal corticosteroid injection for chronic low back pain

Modic I vertebral end‐plate signal changes detected by magnetic resonance imaging (MRI) are associated with chronic low back pain. Typically, Modic I signal changes in untreated patients switch to non–Modic I signal changes within 3 years, which reflect spontaneous healing. Recent findings suggest that Modic I signal changes may be related to local inflammatory changes, providing a rationale for treatment with intradiscal injections of antiinflammatory drugs. In the present report, we describe a 31‐year‐old man with 1‐year history of chronic low back pain associated with vertebral end‐plate Modic I signal changes, who received 1 intradiscal corticosteroid injection in L5–S1. Local treatment led to rapid pain relief and was associated with an accelerated switch from Modic I to Modic 0 signal changes, as seen on lumbar MRI at 1‐month followup. This is the first report of an effective local treatment for both the symptoms and the structural changes of chronic low back pain that are associated with Modic I signal changes. Additionally, this case reinforces the hypothesis that local inflammation has a pathogenic role.     

Evaluating pain and the quality of life in chronic pancreatitis

Summary Chronic pancreatitis is a painful disease, ranging between uncomplicated courses with recurrent pain but longer pain-free intervals and complicated courses with constant intractable pain or frequent severe attacks of pain. Several factors, including intrapancreatic and extrapancreatic abnormalities, contribute to pain in chronic pancreatitis, and their relative contribution may vary from patient to patient. The natural course of pain is modified by the use of analgesic drugs, by interventional treatment modalities, and by operative procedures. Since standards for the evaluation are lacking, treatment results have been evaluated following very different scales and protocols. Interdisciplinary controlled clinical trials comparing interventional and operative treatment are not yet available. For future studies, it seems necessary to recruit patients following a standardized clinically based staging system, to assess treatment results following standardized measures for pain and quality of life. For these purposes, such a staging system is proposed, and the application of the European Organization for Research and Treatment of Cancer (EORTC) quality of life (QLQ) questionnaire is suggested.     

Managing chronic pain in adults with haemophilia: current status and call to action

Haemophilic arthroses are associated with acute pain during bleeding episodes and with chronic pain caused by arthritic complications of repeated bleeding into joints. Unlike other conditions (e.g. osteoarthritis, rheumatoid arthritis, sickle cell disease), there are limited data on pain management in haemophilia. Management of arthritic individuals and those with sickle cell disease relies heavily on administration of acetaminophen, non‐steroidal anti‐inflammatory drugs (NSAIDs) and opioid analgesics. In haemophilia, acetaminophen often has limited efficacy at therapeutic doses, offering a narrow dosing range in those with liver disease due to chronic hepatitis C. NSAIDs can effectively manage pain in patients with haemophilia, but these agents are potentially associated with a significant risk of precipitating or exacerbating bleeding complications in an already coagulopathic population. Opioids have proven effective in osteoarthritis and sickle cell disease, but outcomes data in those with haemophilia are virtually non‐existent. Patients with haemophilia are at least as vulnerable as other chronic pain populations to opioid‐related adverse events and to developing abusive behaviours and addiction. Despite pain management strategies for patients with haemophilia being far from optimal, the predominant precept of haemophilia management still applies. As such, it is critically important to aggressively reverse or prevent acute symptomatic bleeding in a timely and effective manner to at least minimize pain and progressive joint damage. This review should serve as a call to action to prioritize pain management in haemophilia care and spur interest in the development, improvement and standardization of tools to assess and manage acute and chronic pain in haemophilia.     

Gout:A clinical overview and its association with cardiovascular diseases

Gout is a common disease caused by the deposition of monosodium urate(MSU) crystals in patients with hyperuricemia, and characterized by very painful recurrent acute attacks of arthritis. The gold standard for diagnosing gout is the identification of MSU crystals in synovial fluid by polarization light microscopy. Arthritis attacks can be treated with anti-inflammatory medications, such as non-steroidal anti-inflammatory drugs, colchicine, oral prednisone, or intra-articular or intramuscular glucocorticoids. To prevent gout uric acid lowering therapy with for example allopurinol can be prescribed. When gout is adequately treated, the prognosis is good. Unfortunately, the management of gout patients is often insufficient. Gout is associated with dietary factors, the use of diuretics, and several genetic factors. Comorbidities as hypertension, chronic kidney disease, cardiovascular diseases, the metabolic syndrome, diabetes, obesity, hyperlipidemia, and early menopause are associated with a higher prevalence of gout. Xanthine oxidase and chronic systemic inflammation seem to play an important role in the pathophysiology of the association between gout and cardiovascular diseases. To prevent cardiovascular diseases goutpatients must be early screened for cardiovascular risk factors.     

Clomiphene-induced acute pancreatitis without hypertriglyceridemia

Acute pancreatitis may be caused by drugs. In the literature, there are more than 260 different drugs that have been blamed for causing pancreatitis. Among these drugs, only 1 case has been reported as clomiphene-induced acute pancreatitis. However, in this single case, there was concomitant hypertriglyceridemia. We report the case of a woman who developed 2 attacks of acute pancreatitis without hypertriglyceridemia while receiving treatment with clomiphene.