Erythropoietic protoporphyria: case reports for clinical and therapeutic hints.

BACKGROUND: Erythropoietic protoporphyria is a rare disorder which represents an important health problem in children, causing painful photosensitivity. Little is known on the correlation between genetic profile and clinical manifestations. The standard of care for Erythropoietic protoporphyria is based on avoiding sun and using sun protections, but recent literature has suggested that cimetidine may have a role in improving sun sensitivity. Herein we report our case series describing the successful use of cimetidine and analyzing potential phenotype-genotype correlations. CASE PRESENTATION: This case series describes five patients presented to our Rheumatology Service complaining sun sensitivity. Blood exams and genetic analysis were consistent with the diagnosis of erythropoietic protoporphyria. Four of 5 patients received cimetidine in addition to standard therapies and the effect of treatment was evaluated by Erythropoietic Protoporphyria - Quality of Life questionnaire. CONCLUSIONS: Erythropoietic protoporphyria usually manifests in early childhood after a short sun exposure. Skin manifestations are the main reason for investigations, although sometimes they can be more subtle, leading to a significant diagnostic delay. Skin diseases in children can have profound effects on their family and social relationships. A treatment with cimetidine appears to be an excellent therapeutic option in children with Erythropoietic protoporphyria.

Endothelial Dysfunction in Acute Hepatic Porphyrias.

Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the most dramatic manifestations, patients are at risk of developing long-term complications, several of which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to cause most clinical symptoms. Aim We measured the serum levels of endothelin-1 (ET-1) and nitric oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC). Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients. AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest heme precursor urinary levels had the greatest alterations in ED markers, although no significant correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs than to their classical biochemical alterations. Some still undefined disease modifiers may possibly determine the clinical picture of AHPs through an effect on endothelial functions.

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives.

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, [Formula: see text]-aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

Laboratory Diagnosis of Porphyria.

Porphyrias are a group of diseases that are clinically and genetically heterogeneous and originate mostly from inherited dysfunctions of specific enzymes involved in heme biosynthesis. Such dysfunctions result in the excessive production and excretion of the intermediates of the heme biosynthesis pathway in the blood, urine, or feces, and these intermediates are responsible for specific clinical presentations. Porphyrias continue to be underdiagnosed, although laboratory diagnosis based on the measurement of metabolites could be utilized to support clinical suspicion in all symptomatic patients. Moreover, the measurement of enzymatic activities along with a molecular analysis may confirm the diagnosis and are, therefore, crucial for identifying pre-symptomatic carriers. The present review provides an overview of the laboratory assays used most commonly for establishing the diagnosis of porphyria. This would assist the clinicians in prescribing appropriate diagnostic testing and interpreting the testing results.

Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement. OBJECTIVE: To provide epidemiological data of EPP in Italy. MATERIALS & METHODS: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017). RESULTS: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed. CONCLUSION: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.

Hyperhomocysteinemia in patients with acute porphyrias: A potentially dangerous metabolic crossroad?

BACKGROUND: Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic 5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly, both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate, PLP) an important cofactor of ALAS1 and of cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Moreover, heme itself is an important cofactor for CBS. AIM: to assess plasma Hcy status and HHcy main determinants in patients with AP. MATERIALS AND METHODS: A total of 46 patients with AP (31 with Acute Intermittent Porphyria,15 with Variegate Porphyria) were assessed for clinical status (symptomatic vs. asymptomatic), serum Hcy, Cysteine (Cys), Vit.B6, Vit.B12, red blood cell folates and urinary delta-aminolevulinic acid (ALA) and porphobilinogen(PBG) levels (mean of six measurements). RESULTS: Symptomatic AP patients had significantly higher urinary ALA and PBG levels, plasma Hcy, HHcy prevalence and Hcy/Cys ratio when compared to asymptomatic carriers of AP. Even though no significant correlation was observed between ALA/PBG urinary levels and serum Hcy levels, patients with higher levels of ALA and PBG had significantly higher levels of Hcy, a higher prevalence of moderate-to severe HHcy and serum PLP levels below the 25th percentile of a reference assessment with 300 healthy Italian subjects(<45nmol/L). CONCLUSIONS: Most patients with symptomatic AP present HHcy resulting from alterations in sulphur amino acid metabolism. HHcy may represent an indirect marker of ALAS1 induction and its prevalence may be suggestive of a role of HHcy in the pathogenesis and/or comorbidities of AP.

Hyperhomocysteinemia and MTHFR C677T polymorphism in patients with portal vein thrombosis complicating liver cirrhosis.

BACKGROUND: Portal vein thrombosis (PVT) is serious complication of liver cirrhosis (LC), especially in the presence of hepatocellular carcinoma (HCC). The liver plays a key role in homocysteine (Hcy) metabolism: mild hyperhomocysteinemia (HHcy) has been described in LC. HHcy is a risk factor for deep vein thrombosis. Methylen-tetrahydrofolate-reductase (MTHFR) C677T polymorphism is the commonest determinant of mild HHcy and has been involved also in cancer development. AIM: To investigate a possible relation between HHcy, MTHFR status, HCC and PVT in patients affected by LC. MATERIALS AND METHODS: 100 patients affected by LC, 38 with (PVT group, 24 with HCC) and 62 without PVT (LC group, 14 with HCC) sex-, age-, liver disease stage and etiology-matched were assessed for thrombophilia, smoking status, plasma Hcy, MTHFRC677T polymorphism and homocysteine-related vitamin status. RESULTS: A higher prevalence of HCC, HHcy and MTHFR TT status was observed in PVT group. No significant difference in vitamin status was observed between groups. Patients with HCC showed significantly higher plasma Hcy and higher prevalence of HHcy than patients without HCC. They had also higher prevalence of MTHFR TT status. In patients with TT status (n=11) and HCC, 10 had HHcy e 9 had PVT. CONCLUSIONS: Mild HHcy is associated to LC may have a role in PVT development and assessment of plasma Hcy may be suggested in patients with LC (especially if complicated by HCC). Association between HCC and MTHFR TT status is intriguing, due the postulated role for this polymorphism in cancer: it may represent a possible link between HCC and PVT.

Hyperhomocysteinaemia in chronic liver diseases: role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics.

BACKGROUND/AIMS: The liver plays a key role in sulphur aminoacid metabolism hence, homocysteine metabolism may be impaired in chronic liver diseases. The aim of this study was to investigate, in patients affected by chronic liver diseases, (1) the prevalence of hyperhomocysteinaemia and (2) the role of its determinants such as the stage and the aetiology of disease, vitamin status, genetic documented alterations (methylenetetrahydrofolate reductase deficiency) and presence/absence of documented malignant evolution (hepatocellular carcinoma). MATERIAL AND METHODS: One hundred and thirty patients with chronic liver disease (34 with chronic active hepatitis, 12 with fatty liver and 88 with liver cirrhosis) and 50 healthy age-matched control subjects were included into the study. RESULTS: Hyperhomocysteinaemia was defined as homocysteine plasma levels greater than 12.6 micromol/l. Hyperhomocysteinaemia prevalence in liver cirrhosis group was 40.9%, significantly higher (all P<0.01) with respect to controls (12%), chronic active hepatitis (14.7%) and fatty liver (25%) groups and increased with Child-Pugh stage [Child A: 22.2%, Child B (50%); Child C (58.3%)]. In chronic-active hepatitis and liver cirrhosis, the prevalence of subjects with methylenetetrahydrofolate reductase C677-->T mutation (both as CT and as TT) and hyperhomocysteinaemia results in significantly higher levels with respect to controls. Methylenetetrahydrofolate reductase C677-->T mutation and disease stage showed to be the most important predictive factors of hyperhomocysteinaemia in liver cirrhosis whereas the influence of homocysteine-related vitamin status seems to have a secondary role. CONCLUSIONS: In conclusion hyperhomocysteinaemia is highly prevalent in liver cirrhosis but not in other chronic liver diseases; it may contribute to fibrogenesis and vascular complication of liver cirrhosis.