Anticancer chemotherapy in a patient with prior history of acute intermittent porphyria

We describe the case of a patient with a prior history of acute intermittent porphyria (AIP) who needed the administration of anticancer drugs. Our experience with this patient and the limited experience reported in the literature show that it is probably safe to administer some chemotherapeutic agents, but it is important to prevent (or to minimize) the toxicities of these chemotherapeutic agents, as they seem to put the patient at major risk of an AIP crisis. Hematin and supportive treatments were useful treatments in our patient.     

Changes of myocardial functions in acute hepatic porphyrias. Role of heme arginate administration

In three patients with attacks of acute intermittent porphyria we found markedly impaired functions of the left ventricle accompanied by ECG changes that returned to normal after administration of heme arginate or cytochrome C administration. In nine patients with other types of porphyria, and in one patient with acute intermittent porphyria not suffering an attack, no significant changes of left ventricle function were observed. The changes seen in patients with an acute attack may be ascribed to acute myocardial hypoxia resulting from defective biosynthesis of heme. We assume that the exogenous supply of heme may improve cellular hypoxia.     

Quantitation of 3-ethyl-5-hydroxy-4,5-dimethyl-Δ3-pyrrolin-2-one in the urine of patients with acute intermittent porphyria

Abstract. The monopyrrole 3-ethyl-5-hydroxy-4,5-dimethyl-Δ³-pyrrolin-2-one (hydroxyhaemopyrrolin-2-one) has been quantitated in the urine of eight patients with acute intermittent porphyria in attack or remission and ten subjects latent for the disorder. Previous qualitative investigations had revealed an association between hydroxyhaemopyrrolin-2-one excretion and certain psychiatric disorders including acute porphyria.
Urinary excretion of hydroxyhaemopyrrolin-2-one was significantly elevated in patients with acute intermittent porphyria in attack or remission and in latent subjects. No significant difference could be found between the excretion in attack or remission and latency.
A significant association was found in all subjects between urinary hydroxyhaemopyrrolin-2-one concentrations and the urinary excretion of the porphyrin precursors δ-aminolaevulinic acid and porphobilinogen. There was also found to be a linear relationship between the excretion of δ-aminolaevulinic acid and of porphobilinogen.
Excretion of hydroxyhaemopyrrolin-2-one, δ-aminolaevulinic acid and porphobilinogen was also followed in one subject throughout the duration of an acute attack.
The significance of the findings are discussed in relationship to a possible role of hydroxyhaemopyrrolin-2-one in the manifestations of acute porphyria.     

Normeperidine-induced seizures in hereditary coproporphyria

Seizures are common in acute exacerbations of hepatic porphyria, even though the etiology is not identified in most cases. We have reported a case of normeperidine-induced seizures in a patient with hereditary coproporphyria. Although meperidine is commonly used for pain control during acute attacks in these patients, this report suggests that meperidine is not a good analgesic choice in porphyria. Normeperidine-induced seizures in patients with porphyria may be treated by withdrawal of meperidine therapy and selective use of anticonvulsants.     

Pneumonia

Abstract

The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic “bottleneck” in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.     

International air travel: a risk factor for attacks in acute intermittent porphyria

Five patients are reported with acute intermittent porphyria in whom attacks were apparently precipitated by international air travel. In four subjects this was the initial presenting attack and in a fifth the cause of an acute relapse in a patient requiring regular haem arginate prophylaxis. Multifactorial precipitants implicated include, dehydration, missed meals, alcohol use, infection, chronic hypoxia, premenstrual syndrome and stress. Acute intermittent porphyria should be suspected in individuals presenting with unexplained acute abdominal pain following international air travel. Appropriate precautions may reduce the incidence of attacks in known porphyrics.     

Hepatic porphyrias. Current concepts.

Acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria are hepatic porphyrias due to enzyme defects that are inherited as autosomal dominants. Porphyria cutanea tarda is considered an acquired disorder. Similar drugs or circumstances are precipitants of acute attacks in all three inherited hepatic porphyrias. The respective biochemical abnormalities are identifiable by simple, readily available laboratory tests. Management of patients with any of the inherited hepatic porphyrias is directed primarily toward prevention of attacks through avoidance of precipitants and through a diet high in carbohydrate. Therapy for porphyria cutanea tarda includes interdiction of alcohol use and repeated phlebotomy.     

Treatment for irritable bowel syndrome--psychotropic drugs, antidepressants and so on

Irritable bowel syndrome (IBS) is a functional disease with good prognosis, which is diagnosed by exclusion of possible causative organic diseases. However, since the patients tend to have strong psychotic symptoms including anxiety, tension, depression, irritation and insomnia, this syndrome has to be elucidated as a psychosomatic disease. Although the symptoms are usually limited to gastrointestinal symptoms such as abdominal pain and abnormal bowel movements, many patients also manifest some kinds of psychiatric abnormalities such as hypochondria, depression, hysteria, panic disorder and posttraumatic stress disorder. Especially, the prevalence of depression is high. Therefore, use of psychotropic drugs is efficient in treating IBS. Antidepressant agents including tricyclic agents such as amitriptyline, trimipramine, imipramine, clomipramine, amoxapine and nortriptyline; tetracyclic antidepressant; antidepressants such as SSRI and SNRI; sulpiride; benzodiazepine class anxiolytic agents; tandospirone; and Chinese herbal medicine are being used. IBS is a stress-related disease. Therefore, in spite of the importance of pharmacotherapy, patients should also be instructed to avoid the stress that aggravates the symptoms in all aspects of daily life.     

Clinical manifestations of porphyrin metabolism disorders

AIM: To characterize patients with various nosological unities [symbol: see text] of porphyria in accordance with their age, clinical symptoms, provoking factors, therapy and outcome. MATERIAL AND METHODS: Patients with acute intermittent porphyria (43), hereditary coproporphyria (8), variegate porphyria (3), porphyria cutanea tarda (7), hepatoerythropoietic porphyria (1), and hereditary erythropoietic porphyria (2) were studied. One patient was suspected of porphyria caused by deficiency of delta-aminolevulenic acid dehydrogenase. RESULTS: The patients were from the CIS. The overwhelming majority of them were young and middle-aged subjects. Rapid development of the disease and severe neurological symptoms were predominantly observed in patients with acute forms of porphyria. CONCLUSION: Early diagnosis of porphyrin metabolism disorders makes it possible to decrease abruptly the number of cases leading to severe complications, disability, and fatal outcome. The use of inexpensive methods of screening of porphyrin metabolism disorders provides a promising approach to solving this problem. These methods should be used in municipal hospitals. In addition, asymptomatic carriers of defective gene should be revealed at the preclinical stage using various methods of molecular genetic assay.     

Uroporphyrinogen synthase in erythrocytes in acute intermittent porphyria: new pathobiochemical aspects (author's transl)

Uroporphyrinogen synthase (EC 4.3.1.8) was determined in the erythrocytes of 380 patients, of which 21 showed clinical symptoms of acute intermittent porphyria. The normal range of a random sample was 61 +/- 23 mumol/1.h(x +/- 2s, n=302), including the activity of uroporphyrinogen cosynthase and the subsequent enzymes; when all the latter enzymes were destroyed by heating the haemolysate, the normal range for uroporphyrinogen synthase was 65 +/- 25 mumol/1.h(x +/- 2s, n=274). The respective activity of uroporphyrinogen synthase in patients with acute intermittent porphyria was 35 +/- 12, and 40 +/- 18 mumol/1.h which was significantly lower (p less than 0.001) than the control values. In the 21 cases of acute intermittent porphyria, the diagnosis had already been made from the presence of porphyrin precursors and porphyrin in the urine. In 7 of the 21 cases of acute intermittent porphyria, and in 6 relatives of the patients, the activity of the uroporphyrinogen synthase was in the overlap zone (40-50 mumol/1.h). 32 relatives of 9 of the patients with acute intermittent porphyria were investigated: 22 showed a significant decrease of uroporphyrinogen synthase, and 7 of these showed pathological urinary porphyrin precursors and porphyrin. The relative activity of uroporphyrinogen synthase in patients with acute intermittent porphyria was 57%. A decrease of the uroporphyrinogen synthase activity of greater than 30% compared with the mean of the controls is a sure indicator for the presence of a primary enzymic defect in the gene carrier for acute intermittent porphyria.     

Depression in medical practice

Depressive symptoms may be produced by many drugs and diseases. A physical examination, systems review and medical history should be included in the evaluation of any patient presenting with depressive symptoms. The same criteria for major depression should be applied to patients in psychiatric and nonpsychiatric settings. Tricyclic agents may be effective in treating depressive symptoms associated with medical illness.     

In pursuit of perfection: a primary care physician's guide to body dysmorphic disorder.

Body dysmorphic disorder is an under-recognized chronic problem that is defined as an excessive preoccupation with an imagined or a minor defect of a localized facial feature or body part, resulting in decreased social, academic and occupational functioning. Patients who have body dysmorphic disorder are preoccupied with an ideal body image and view themselves as ugly or misshapen. Comorbid psychiatric disorders may also be present in these patients. Body dysmorphic disorder is distinguished from eating disorders such as anorexia nervosa that encompass a preoccupation with overall body shape and weight. Psychosocial and neurochemical factors, specifically serotonin dysfunction, are postulated etiologies. Treatment approaches include cognitive-behavioral psychotherapy and psychotropic medication. To relieve the symptoms of body dysmorphic disorder, selective serotonin reuptake inhibitors, in higher dosages than those typically recommended for other psychiatric disorders, may be necessary. A trusting relationship between the patient and the family physician may encourage compliance with medical treatment and bridge the transition to psychiatric intervention.     

Psychiatric symptoms in endocrine diseases. Keys to identifying the underlying disorder

Several important points should be considered regarding psychiatric symptoms in endocrine disorders. The presence of cognitive deficits in a patient presenting with anxiety, depression, or another apparently "functional" psychiatric complaint should raise the index of suspicion of organic etiology, with endocrine disorders high on the list. Psychiatric symptoms secondary to endocrine disturbance generally reverse, albeit slowly, with treatment of the primary hormonal abnormality. When significant disruption of cognitive functioning is evident, residual deficits may develop. Treatment with psychotropic agents for symptomatic relief of psychiatric complaints should be undertaken with great caution in patients with endocrine disorders.     

New drugs in psychiatry

Recent years have witnessed the rapid expansion of new psychotropic agents and psychotropic applications of primarily nonpsychiatric medications in nearly all domains of psychopathology. Increasingly, patients in emergency departments may be taking newer-generation antidepressants, antipsychotics, and mood-stabilizing drugs, and individuals with treatment-resistant psychiatric disorders are often prescribed complex, polypharmaceutical regimens. Current information on the use of psychiatric medications that have entered widespread use in the past 5 to 10 years is reviewed, with focus on indications and dosing, comparisons with older medications, management of patients with overdoses and toxicity states, and the medical and psychiatric effects of newer drugs on patients who may present to emergency departments.     

Induction of a deficiency of steroid delta 4-5 alpha-reductase activity in liver by a porphyrinogenic drug.

The hepatic enzymes that catalyze drug oxidations and the reductive metabolism of steroid hormones to 5alpha-derivatives are localized in membranes of the endoplasmic reticulum. Phenobarbital, which exacerbates acute intermittent porphyria in man, induces drug-oxidizing enzymes in liver. Additionally, patients in whome the primary gene defect (uroporphyrinogen-I-synthetase deficiency) of acute intermittent porphyria has become clinically expressed have low levels of hepatic steroid delta4-5alpha-reductase activity. This 5alpha-reductase deficiency in acute intermittent porphyria leads to the disproportionate generation of 5beta-steroid metabolites from precursor hormones; such steroid metabolites have significant porphyria-inducing action experimentally. In this study the effects of phenobarbital on drug oxidation and steroid 5alpha-reduction in man were examined to determine if this drug could produce changes in steroid 5alpha-reductase activity which mimicked those seen in patients with acute intermittent porphyria. Metabolic studies with [14C]-testosterone and 11beta-[3H]hydroxyandrostenedione were carried out in five normal volunteers. In all five subjects phenobarbital administration (2 mg/kg/per day for 21 days) enhanced plasma removal of the test drugs antipyrine and phenylbutazone as expected; but in four subjects phenobarbital also substantially depressed 5alpha-metabolite formation from [14C]testosterone and resulted in a pattern of hormone biotransformation characterized by a high ratio of 5beta/5alpha-metabolite formation. Studies with 11beta-[3H]hydroxy-androstenedione in three subjects confirmed that phenobarbital produced this high 5beta/5alpha ratio of steroid metabolism by depressing 5alpha-reductase activity for steroid hormones in liver. The high ratio of 5beta/5alpha-metabolites formed in normals after drug treatment mimicks the high 5beta/5alpha-steroid metabolite ratio formed from endogenous hormones in acute intermittent porphyria. The proximate mechanism by which phenobarbital induces reciprocal changes in activities of the microsomal enzymes which catalyze drug oxidations and steroid 5alpha-reductions is not known. This action of phenobarbital raises the possibility, however, that certain drugs which provoke exacerbations of human porphyria may do so, in part, by producing deleterious shifts in the patterns of endogenous steroid hormone metabolism.     

Denaturing gradient gel electrophoresis for rapid detection of latent carriers of a subtype of acute intermittent porphyria with normal erythrocyte porphobilinogen deaminase activity.

Acute intermittent porphyria is an autosomal dominant disorder defined by a partial deficiency of porphobilinogen deaminase (EC 4.3.1.8). Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often linked to environmental factors. Early diagnosis of gene carriers is important in the prevention of attacks and is usually achieved by determining the porphobilinogen deaminase activity in erythrocytes. However, in a subtype of acute intermittent porphyria, the enzymatic defect is restricted to nonerythropoietic cells. Different mutations have already been described that account for this phenotype in two unrelated families. We previously detected asymptomatic carriers by using mutation-specific probes after in vitro amplification of the target DNA sequence. In this study, we investigated the DNA of eight unrelated subjects with the same subtype of acute intermittent porphyria by using the polymerase chain reaction, with subsequent analysis of the amplified products by denaturing gradient gel electrophoresis. Five of these patients shared the same single-base change. This technique was quite simple and efficient for detecting asymptomatic carriers. Importantly, it is potentially useful for studying families with the same phenotypic subtype of the disease and possibly different mutations in the same DNA region.     

Variant of acute intermittent porphyria with normal erythrocyte uroporphyrinogen-I-synthase activity

A kindred in which several members have otherwise typical acute intermittent porphyria but normal erythrocyte uroporphyrinogen-I-synthase activity has been described from Finland. We studied two porphyric members of this kindred, two patients with typical acute intermittent porphyria, and two healthy controls using the delta-aminolaevulinic acid loading test and by measuring the erythrocyte enzymes of haem biosynthesis. The excretion pattern of haem precursors after the delta-aminolaevulinic loading test in the members of the kindred studied, was similar to that in typical acute intermittent porphyria suggesting an identical enzyme defect in the liver. The activity of all red cell enzymes studied was normal in the members of the kindred. The results suggest that porphyria in the kindred studied is a variant of acute intermittent porphyria, where the uroporphyrinogen-I-synthase defect is manifested in the liver but not in red cells.     

ED presentation of acute porphyria

Abdominal pain is a common complaint for visits to ED. Among the causes of abdominal pain, the acute porphyria may confuse emergency physicians. With wide range of unspecific symptoms and signs, acute porphyria is rarely considered as a differential diagnosis of acute abdomen in ED. Some patients even receive unnecessary surgery. There are 32 patients who visited the ED of National Taiwan University Hospital because of acute porphyric attacks over the past 13 years. Ten patients (3 males and 7 females) were diagnosed with acute porphyria for the first time at ED. The onset of age ranged from 17 to 55 years (mean, 32 years). All of our patients presented with abdominal pain but without fever, dermatologic, and neurologic symptoms that are typically presented in acute porphyria. On the average, most of them repeatedly sought for medical help because of persistent symptoms for 4 times before being definitely diagnosed and thus receiving the optimal treatment. Meanwhile, all patients needed at least 2 kinds of analgesic, and most of them needed narcotic analgesia for pain control before diagnosis. The most commonest point of tenderness is over epigastrium (7 of 10 patients). The laboratory and image studies of our patients were of no diagnostic value for acute porphyria, except for Watson-Schwartz test. In summary, our study revealed that when a patient after puberty with repetitive visits because of severe abdominal pain without reasonable causes and needs narcotics for pain control, acute porphyria should be taken into consideration.     

Drugs in porphyria: From observation to a modern algorithm-based system for the prediction of porphyrogenicity

The acute porphyrias are a group of disorders which result from inherited defects in the enzymes of the heme biosynthetic pathway. Affected patients are prone to potentially fatal acute attacks. These attacks are frequently precipitated by exposure to commonly used drugs. Correctly identifying the safety or otherwise of drugs in porphyria is therefore important. In this review we describe how clinical experience and the findings of experimental systems using whole animal or cell culture models have been interpreted to determine porphyrogenicity, that is the potential of a drug to induce an acute attack in a patient carrying a gene for acute porphyria.It is now well established that induction of delta-aminolevulinic acid synthase, the rate controlling enzyme of the heme biosynthetic pathway, is fundamental to porphyrogenicity, and that drug-induced hepatic heme depletion via induction or suicidal inactivation of cytochrome P450 is central to this process. The process is now sufficiently well understood that prediction of porphyrogenicity from structural and functional information alone would appear to be justified.