Ulrich Gross

Bio: Ulrich Gross is an academic researcher from University of Marburg. The author has contributed to research in topics: Porphyria & Acute intermittent porphyria. The author has an hindex of 9, co-authored 11 publications receiving 300 citations.

Alcohol and porphyrin metabolism.

Abstract: “Ethanol should be included in the list of drugs metabolized by hepatic microsomes” (Rubin and Lieber 1972) Such drugs stimulate their own metabolism, in which heme synthesis is involved, and affect porphyrin synthesis in various ways Alteration of porphyrin synthesis in an organism without hereditary and acquired toxic disturbances of porphyrin metabolism is an adaptive response Generally, these adaptive responses elicited by alcohol or other drugs in an organism without preexistent derangements in the heme biosynthesis sequences do not lead to clinical consequences However, certain drugs, including alcohol, are capable of expressing not only the latent but also the clinical phase of different porphyrias Especially acute hepatic porphyrias are triggered by drugs and/or alcohol and have therefore been designated as “pharmacogenetic diseases” (Kalow 1962) In addition, alcohol is the most frequent manifesting and aggravating factor in chronic hepatic porphyria, including porphyria cutanea tarda, which is genetically predetermined in some of the patients (Doss 1982; Kushner 1982) The clinical-biochemical interactions between alcohol and porphyrin/heme biosynthesis involve three main aspects: 1 Triggering the biochemical and clinical manifestation of acute and chronic hepatic porphyrias 2 Development of symptomatic disturbances in porphyrin metabolism as secondary coproporphyrinuria and secondary protoporphyrinemia 3 Inhibition and stimulation of certain enzymes in the heme biosynthetic chain

Hepatic complications of erythropoietic protoporphyria

Abstract: A quarter of patients with erythropoietic protoporphyria develop mild to severe cholestatic liver disease. The determination of early indicators of hepatobiliary involvement are of pivotal importance to select patients for choleretic therapy. Porphyrin parameters were studied during ursodeoxycholic acid treatment in eight patients with protoporphyrin-associated liver disease and eight patients with liver failure before and after liver transplantation. The patients with intrahepatic cholestasis exhibited excessive protoporphyrinemia (27 μmol/l) compared with controls (normal 71±10%, and reduction of fecal protoporphyrin excretion. Results suggest that therapy of intrahepatic cholestasis with ursodeoxycholic acid is only effective in the initial stages of liver disease in erythropoietic protoporphyria. In patients with severe cholestatic hepatic failure, liver transplantation is the treatment of choice.

5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up

Abstract: 5-Aminolevulinic acid dehydratase (ALAD) activity in two patients with compound heterozygous 5-aminolevulinic acid dehydratase deficiency porphyria was studied over the last 20 years. The patients' enzyme activity was <10% from 1977 to 1997. An acute crisis in each patient was successfully treated by infusion of glucose and heme arginate. After this therapy both urinary 5-aminolevulinic acid (ALA) and total porphyrins were diminished to 65% in patient B. In patient H, ALA was decreased to 80%, and total porphyrins were reduced to 15% after treatment with heme arginate and glucose. The patients remained free of symptoms after this therapy. Family studies of patient B showed cross-reactive immunological material (CRIM), in which the maternal mutation is CRIM(+), whereas the paternal mutation is CRIM(-). Incubation of erythrocyte lysates with ALA decreased porphyrin formation, whereas incubation with porphobilinogen produced porphyrin concentrations within reference values in both patients, confirming that ALAD activity is rate-limiting in these cells.

Immunological, enzymatic and biochemical studies of uroporphyrinogen III-synthase deficiency in 20 patients with congenital erythropoietic porphyria.

Abstract: Congenital erythropoietic porphyria (CEP), a rare autosomal recessive inborn error of heme biosynthesis, results from reduced activity of uroporphyrinogen III synthase (URO-III-S) leading to an excessive production and accumulation of porphyrins. Various clinical and biochemical observations point to a relationship between degree of disease expression and metabolic disturbance. We investigated 20 patients with early onset of clinical symptoms of CEP and, additionally, the relatives of six patients. CEP was confirmed by porphyrinemia and porphyrinuria with dominance of uroporphyrin and its isomer I. The investigation of the immunological nature of the defective URO-III-S gene from unrelated patients with unknown mutations was possible thanks to an antibody against the human enzyme. URO-III-S concentration in erythrocytes was determined by ELISA. No signal was achieved when assaying nonimmune serum by ELISA, whereas there was a positive reaction with the serum after immunisation. Furthermore, specificity of immune sera is demonstrated by immunoprecipitation of URO-III-S activity which caused a 33 % reduction of enzyme activity. Normal levels of immunoreactive enzyme protein 100 ± 10 % of control (x¯ ± SD, n = 12) with a reduced specific activity 15 ± 8.5 % (x¯ ± SD, n = 12) were found in erythrocytes from all patients, with the exception of a girl with a remarkably high enzyme concentration of 149 % of controls and a very low specific activity of 4 %. In consequence, all patients had cross-reacting immunological material (CRIM)-positive mutations. CRIM-ratios varied between 3.2 and 24.5. The CRIM-positive nature of the gene defect indicated that the mutations altered the activity of URO-III-S. The different CRIM ratios implied the presence of various mutations, which is further evidence for the heterogeneity in the genetic defect found in CEP. URO-III-S activity was determined in erythrocyte lysates by a coupled enzyme assay. Erythrocyte URO-III-S activities of patients were reduced to 4−33 % of the normal value (1.72 ± 0.14 pkat/mg protein). An increase of urinary coproporphyrin isomer I (40−61 %, norm = 17−31 %) and a halved URO-III-S activity can serve as a biochemical test for asymptomatic heterozygous gene carriers of CEP.

Modern diagnosis and management of the porphyrias

Abstract: Recent advances in the molecular understanding of the porphyrias now offer specific diagnosis and precise definition of the types of genetic mutations involved in the disease. Molecular diagnostic testing is powerful and very useful in kindred evaluation and genetic counselling when a disease-responsible mutation has been identified in the family. It is also the only way to properly screen asymptomatic gene carriers, facilitating correct treatment and appropriate genetic counselling of family members at risk. However, it should be noted that DNA-based testing is for the diagnosis of the gene carrier status, but not for the diagnosis of clinical syndrome or severity of the disease, e.g. an acute attack. For the diagnosis of clinically expressed porphyrias, a logical stepwise approach including the analysis of porphyrins and their precursors should not be underestimated, as it is still very useful, and is often the best from the cost-effective point of view.

Protoporphyrin IX: the Good, the Bad, and the Ugly.

Abstract: Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

An update of clinical management of acute intermittent porphyria.

Abstract: Acute intermittent porphyria (AIP) is due to a deficiency of the third enzyme, the hydroxymethylbilane synthase, in heme biosynthesis. It manifests with occasional neuropsychiatric crises associated with overproduction of porphyrin precursors, aminolevulinic acid and porphobilinogen. The clinical criteria of an acute attack include the paroxysmal nature and various combinations of symptoms, such as abdominal pain, autonomic dysfunction, hyponatremia, muscle weakness, or mental symptoms, in the absence of other obvious causes. Intensive abdominal pain without peritoneal signs, acute peripheral neuropathy, and encephalopathy usually with seizures or psychosis are the key symptoms indicating possible acute porphyria. More than fivefold elevation of urinary porphobilinogen excretion together with typical symptoms of an acute attack is sufficient to start a treatment. Currently, the prognosis of the patients with AIP is good, but physicians should be aware of a potentially fatal outcome of the disease. Mutation screening and identification of type of acute porphyria can be done at the quiescent phase of the disease. The management of patients with AIP include following strategies: A, during an acute attack: 1) treatment with heme preparations, if an acute attack is severe or moderate; 2) symptomatic treatment of autonomic dysfunctions, polyneuropathy and encephalopathy; 3) exclusion of precipitating factors; and 4) adequate nutrition and fluid therapy. B, during remission: 1) exclusion of precipitating factors (education of patients and family doctors), 2) information about on-line drug lists, and 3) mutation screening for family members and education about precipitating factors in mutation-positive family members. C, management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in patients with severe recurrent attacks. D, follow-up of the AIP patients for long-term complications: chronic hypertension, chronic kidney insufficiency, chronic pain syndrome, and hepatocellular carcinoma.