Multinodular fatty change in the liver in three patients with chronic hepatic porphyria: Contribution of sonography to the diagnosis.

We present three cases of chronic hepatic porphyria (CHP) in alcoholic patients, in which grayscale ultrasound (US) revealed multiple echogenic masses in the liver, mimicking multinodular hepatocellular carcinoma on alcoholic liver injury. In all cases, contrast-enhanced US (CEUS) showed iso-enhancement of the mass lesions throughout all vascular phases. Additionally, two-dimensional shear wave elastography (2DSWE) (performed in two cases) revealed the mass to have almost the same SWE value as the surrounding parenchyma. When encountering alcoholic patients with multiple echogenic masses in the liver, CHP must be included in the differential diagnosis. CEUS and 2DSWE allow us to increase our diagnostic confidence of CHP.

Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments.

PURPOSE OF REVIEW: Many studies over the past decade have together identified new genes including modifier genes and new regulation and pathophysiological mechanisms in inherited inborn diseases of the heme biosynthetic pathway. A new porphyria has been characterized: X-linked protoporphyria and the perspective to have innovative treatment at very short-term became a reality. We will summarize how recent data on both ALAS1 and ALAS2 have informed our understanding of disease pathogenesis with an emphasis on how this information may contribute to new therapeutic strategies. RECENT FINDINGS: The development of clinical and biological porphyria networks improved the long-term follow up of cohorts. The ageing of patients have allowed for the identification of novel recurrently mutated genes, and highlighted long-term complications in acute hepatic porphyrias. The treatment of hepatic porphyrias by an RNAi-targeting hepatic ALAS1 is actually tested and may lead to improve the management of acute attacks.In erythropoietic porphyrias, the key role of ALAS2 as a gate keeper of the heme and subsequently hemoglobin synthesis has been demonstrated. Its implication as a modifier gene in over erythroid disorders has also been documented. SUMMARY: The knowledge of both the genetic abnormalities and the regulation of heme biosynthesis has increased over the last 5 years and open new avenues in the management of erythropoietic and acute hepatic porphyrias.

Hepatic porphyria: A narrative review.

Porphyrias are a group of metabolic disorders, which result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway. These have been subdivided based on the predominant site of enzyme defect into hepatic and erythropoietic types and based on clinical presentation into acute neurovisceral and cutaneous blistering porphyrias. This review focuses on hepatic porphyrias, which include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), aminolevulinic acid dehydratase deficiency porphyria (ADP), and porphyria cutanea tarda (PCT). Of these, AIP and ADP are classified as acute porphyria, PCT as cutaneous, while VP and HCP present with both acute and cutaneous clinical manifestations. Porphobilinogen levels in a spot urine sample is the initial screening test for the diagnosis of acute hepatic porphyria, and plasma with spot urine porphyrin levels is the initial screening test to approach patients suspected of cutaneous porphyria. Specific biochemical porphyrin profile for each porphyria helps in determining the specific diagnosis. Pain relief and elimination of triggering agents are the initial steps in managing a patient presenting with an acute attack. Intravenous glucose administration terminates the mild episode of acute porphyria, with intravenous hemin needed for management of moderate to severe episodes. Liver transplantation is curative and may be needed for patients with a life-threatening acute porphyria attack or for patients with recurrent acute attacks refractory to prophylactic treatment. Of the cutaneous porphyrias, PCT is the most common and is frequently associated with a combination of multiple susceptibility factors such as alcohol use, smoking, hepatitis C virus infection, HIV infection, estrogen use, and mutations of the hemochromatosis gene. Regular phlebotomy schedule and low-dose hydroxychloroquine are effective and safe treatment options for management of PCT.

The role of nutrition in dermatologic diseases: facts and controversies.

Many dermatologic diseases are chronic with no definitive cure. For some diseases, the etiology is not completely understood, with treatment being difficult and associated with side effects. In such cases, patients may try alternative treatments to prevent onset, reduce symptom severity, or prevent reoccurrence of a disease. Dietary modification, through supplementation and exclusion, is an extremely popular treatment modality for patients with dermatologic conditions. It is, therefore, important for dermatologists to be aware of the growing body of literature pertaining to nutrition and skin disease to appropriately inform patients on benefits and harms of specific dietary interventions. We address the role of nutrition in psoriasis, atopic dermatitis, urticaria, and bullous diseases and specific dietary modifications as an adjunct or alternative to conventional therapy.

[Hepatic porphyrias with cutaneous symptoms]. / Iho-oireiset hepaattiset porfyriat.

Hepatic porphyrias with cutaneous symptoms Cutaneous symptoms of porphyrias are initiated from a phototoxic reaction caused by sunlight and circulating porphyrins in the vascular walls of the skin. This leads in fragility, blistering and scarring of the skin on light-exposed areas. There are approximately 200 patients having hepatic porphyrias with cutaneous symptoms in Finland. Cutaneous symptoms of variegate porphyria and porphyria cutanea tarda are indistinguishable, but an effective treatment is available only for the latter. Differential diagnosis is important due to acute episodes occurring in variegate porphyria.

Human hereditary hepatic porphyrias.

The human hereditary hepatic porphyrias are diseases due to marked deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias can be classified as either hepatic or erythroid, depending on the major production site of porphyrins or their precursors. The pathogenesis of inherited hepatic porphyrias has now been defined at the molecular level. Some gene carriers are vulnerable to a range of exogenous and endogenous factors, which may trigger neuropsychiatric and/or cutaneous symptoms. Early diagnosis is of prime importance since it makes way for counselling. In this article we present an overview of recent advances on hepatic porphyrias: 5-aminolevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), hereditary coproporphyria (HC), and variegate porphyria (VP).

Haplotype analysis excludes the functional protoporphyrinogen oxidase promoter polymorphism -1081G>A as a modifying factor in the clinical expression of variegate porphyria.

Variegate porphyria (VP) is caused by the founder-type protoporphyrinogen oxidase (PPOX) gene mutation R59W in the majority of South African patients. VP is inherited as an autosomal dominant disease with incomplete penetrance and no genotype-phenotype association has been established to date. In an attempt to determine whether a relatively common mutation in the promoter region of the gene (-1081G>A) represents a low-expression allele that may influence clinical manifestation of the disease when inherited from the non-carrier (R59W-negative) parent, we have studied the effect of the mutated allele using an in vitro luciferase assay. Haplotype analysis was furthermore used to evaluate the added information obtained by considering the possible influence of this mutation in combination with a polymorphism in intron 2 (206G>C) of the gene in a genotype-phenotype correlation study. Although the mutation at nucleotide -1081 resulted in a significant reduction in transcriptional activity relative to the reference wild type, no evidence could be obtained that a specific haplotype inherited from the normal parent affects clinical expression of the disease. We thus conclude that other factors such as modifier loci unrelated to the PPOX gene may determine clinical manifestation of VP.

[Hepatic porphyrias and alcohol]. / Hepatische Porphyrien und Alkohol.

Alcohol has an porphyrinogenic action and can cause a disturbance of porphyrin metabolism in healthy people as well as lead to a biochemical and clinical manifestation of acute and chronic hepatic porphyrias, especially acute intermittent porphyria and porphyria cutanea tarda. After excessive consumption of alcohol a temporary, clinically asymptomatic secondary hepatic coproporphyrinuria in man can be observed, which can become persistent in cases of alcohol-induced liver damage. Nowadays alcohol-liver-porphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism. In people with a genetic lack of uroporphyrinogen-decarboxylase alcohol is able to transform an asymptomatic coproporphyrinuria into a chronic hepatic porphyria or porphyria cutanea tarda. From experimental and clinical studies the conclusion can be drawn that alcohol inhibits the enzymes delta-aminolevulinic-acid-dehydratase (synonym: porphobilinogen-synthase), uroporphyrinogen-decarboxylase and coproporphyrinogen-oxidase and induces delta-aminolevulinic-acid-synthase in the liver. Abstinence of alcohol is a therapeutically and prophylactically important measurement in all types of hepatic porphyrias. For clinical experience follows that in cases with chronic consumption of alcohol, fatty liver, alcohol induced hepatitis and liver cirrhosis porphyrin studies in urine should be made to notice a hepatic porphyria in the latent phase very early. When dealing with abdominal and cutaneous symptoms in clinical context with consumption of alcohol one has to exclude hepatic porphyria differential diagnostically.

Hepatic protoporphyrin metabolism in patients with advanced protoporphyric liver disease.

Protoporphyria is a genetic disorder in which liver damage is caused by the toxic effect of protoporphyrin accumulation in the liver. In this study protoporphyrin was measured in the resected livers of 7 patients who had liver transplantation and an additional patient from whom liver tissue was obtained post mortem. Comparison of liver, erythrocyte and serum protoporphyrin levels demonstrated a marked gradient between these compartments: erythrocyte, 5781 +/- 655 micrograms/dl; serum, 384 +/- 102 micrograms/dl; liver 377,238 +/- 55,568 micrograms/100 gm wet weight, (mean +/- SE). Protoporphyrin levels in bile of 3 patients were 55,559, and 1,153 micrograms/dl, indicating a gradient between liver and bile as well. Examination of the livers by polarization microscopy and electron microscopy demonstrated protoporphyrin pigment crystals. In one patient who had recurrent liver disease after transplantation, the protoporphyrin concentration in the graft at the time of death was similar to that in the resected liver. These data indicate that liver protoporphyrin levels in patients with advanced protoporphyric liver disease are much higher than levels in blood and bile, in part because protoporphyrin forms crystalline deposits in liver tissue. Thus, progressive hepatic accumulation of protoporphyrin occurs in the face of impaired biliary excretion. An intrinsic defect in hepatic excretion of protoporphyrin is probably not necessary for this condition to develop because liver disease can occur in the graft following transplantation.

Late onset variegate porphyria.

Variegate porphyria (VP) first presenting in old age is uncommon and should raise the possibility of an underlying precipitating cause. This case report documents VP in an elderly woman with a liver tumour.

Porfiria hepática con manifestaciones neurológicas

Describimos tres casos de porfiria hepática, resaltando historia familiar, factores precipitantes, signos y síntomas, medios diagnóstico y tratamiento. La porfiria aguda intermitente, coproporfiria hereditaria y la porfiria variegata se caracterizan por manifestaciones agudas gastrointestinales, psiquiátricas y neurológicas. Las porfirias deben ser consideradas en el diagnóstico diferencial de pacientes con neuropatía periférica y episodios severos de dolor abdominal recurrente.

[delta-Aminolevulinate dehydratase deficiency].

delta-Aminolevulinate dehydratase (ALAD: E. C. 4.2.1.24), the second enzyme in the heme biosynthetic pathway, condenses two moles of delta-aminolevulinic acid to form porphobilinogen. ALAD deficiency is well known to develop signs and symptoms of typical hepatic porphyria, and classified into three categories as follows: (i) ALAD porphyria, a genetic defect of the enzyme, (ii) tyrosinemia type I, a genetic defect of fumarylacetoacetase in the tyrosine catabolic pathway, producing succinylacetone (a potent inhibitor of ALAD), and (iii) ALAD inhibition by environmental hazards, such as lead, trichloroethylene, and styrene. In the present article, we will describe molecular and biochemical mechanisms to cause the enzyme defect to discuss the significance of ALAD defect on human health.

[Hereditary coproporphyria (Hepatic coproporphyria), Erythropoietic coproporphyria].

Hereditary coproporphyria (Hepatic coproporphyria: HCP); HCP is the rarest and least recognized among hepatic porphyrias and is characterised by an excess of faecal and urinary excretion of coproporphyrin (mainly isomer III). The deficiency is in coproporphyrinogen oxidase. HCP was first described by Berger and Goldberg in 1955 and was considered an asymptomatic biochemical abnormality. It later became evident that HCP could provoke acute attacks similar to those of acute intermittent porphyria (AIP) and variegate porphyria (VP). Such episodes are often provoked by barbiturates, sulphonamides and other drugs, and include automatic symptoms (hypertension, tachycardia, abdominal pain, constipation), central (epileptic seizures, mental disturbances) and peripheral nervous system dysfunction. During acute attacks, urinary ALA (delta-aminole-vulinic acid) and PBG (porphobilinogen) are elevated just as in AIP and VP, however, a marked elevation of faecal COPRO (coproporphyrin) is diagnostic of HCP. Laparoscopic finding of our case showed a map-like appearance of the liver surface with slightly depressed dark-bluish areas and reddish-brown areas. The liver biopsy specimen showed red fluorescence under ultraviolet light. On HE staining, hydropic degeneration of the hepatocytes and many brown granules in the hepatocytes were seen. A part of the granules stained positive for iron. Schmorl's stain showed many needle-shaped crystallines. Erythropoietic coproporphyria (ECP); Heilmeyer and Clotten have described that elevated PROTO (protoporphyrin) and COPRO were found in the RBC of the patient. Topi et al. described two brothers with cutaneous photosensitivity similar to that of erythropoietic protoporphyria, but with elevated RBC PROTO and COPRO III in both. Very little is known about this disease.

A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria.

Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by a deficient activity of coproporphyrinogen IX oxidase (CPX). We previously described harderoporphyria, a homozygous variant form of coproporphyria in three siblings, characterized by a massive excretion of harderoporphyrin and a marked decrease of coproporphyrinogen IX oxidase activity. In this kindred, the transmission of the disease was autosomal recessive. In the present study, sequencing of cDNA and genomic DNA from these patients revealed a point mutation resulting in a lysine to glutamic acid substitution (K304E) in exon 6 of the gene and the absence of the normal allele, suggesting a homozygous state for the mutation. Expression studies of normal and mutated cDNAs in E. coli demonstrated that this amino acid substitution was responsible for the important decrease in the enzyme activity and for the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal suggesting that the lysine at position 304 is important for binding the substrate: a slightly increased sensitivity to thermal denaturation was also observed.

Fatigue syndromes: new thoughts and reinterpretation of previous data.

Recently, the author has identified 19 patients who have complained of marked fatigue that had abnormal responses to copper test bracelets or necklaces. At this time, 8 have been shown to have at least one enzyme deficiency in the heme pathway. These patients have been diagnosed with multiple sclerosis, chronic fatigue syndrome and other non-specific diagnoses. A lengthy but still limited review of the literature was performed regarding the following conditions: multiple sclerosis (MS), hepatic porphyria (HP), chronic fatigue syndrome (CFS) and paralytic polio (PP). The text will focus on similar epidemiologies, laboratory findings and clinical courses. Copper as a common but not unique etiologic agent will be discussed; as will the heme pathway, a biologic process that may be disordered in all.