Neville R. Pimstone

Recommendations for the Diagnosis and Treatment of the Acute Porphyrias

Key Summary Points Early Diagnosis of Acute Porphyria Consider in all adults with unexplained symptoms seen in acute porphyrias (Table 2); certain clinical features are suggestive: women of reproductive age; abdominal pain; muscle weakness; hyponatremia; and dark or reddish urine. Establish diagnosis promptly by testing for increased porphobilinogen in a single-void urine (we recommend the Trace PBG Kit [Thermo Trace/DMA, Arlington, Texas]). If porphobilinogen is increased, begin treatment immediately. To establish the type of acute porphyria, save the same urine sample for measurement of ALA, porphobilinogen, and porphyrin levels, and measure plasma porphyrin levels, fecal porphyrin levels, and erythrocyte porphobilinogen deaminase levels (Table 5 and Figure). Treatment of the Acute Attack Hospitalize patient for control of acute symptoms and withdraw all unsafe medications (see Table 3) and other possible precipitating factors. Provide nutritional support and symptomatic and supportive treatment; consider seizure precautions, especially if patient is hyponatremic; use medications that are known to be safe in the acute porphyrias; and use intravenous fluids to correct dehydration and electrolyte imbalances, narcotic analgesics for pain, phenothiazine for nausea or vomiting, and -adrenergic blockers for hypertension and symptomatic tachycardia. Begin hemin (3 to 4 mg/kg daily for at least 4 days) as soon as possible. Intravenous glucose alone (10%, at least 300 g daily) may resolve mild attacks (mild pain, no paresis, or hyponatremia) or can be given while awaiting delivery of hemin. Monitor patient closely: Check vital capacity (if impaired, place patient in intensive care) and neurologic status, including muscle strength (especially proximal); check serum electrolytes, creatinine, and magnesium levels at least daily; and watch for bladder distention. Follow-up Educate patient and family about the disease, its inheritance, precipitating factors, and important preventive measures. Encourage patients to wear medical alert bracelets and keep records of diagnostic studies and recommended therapy. Treat chronic manifestations (such as pain and depression) and disability. Provide access to genetic testing for patient and family members. The acute porphyrias are well-defined genetic disorders of heme biosynthesis characterized by acute life-threatening attacks of nonspecific neurologic symptoms (1). Although the specific enzyme and gene defects have been identified, diagnosis and treatment of these 4 disorders still present formidable challenges because their symptoms and signs mimic other, more common conditions. Delaying diagnosis and treatment of acute porphyric attacks can be fatal or can cause long-term or permanent neurologic damage. Updated, consistent recommendations for timely diagnosis and treatment of these disorders have been lacking, despite the existence of rapid, sensitive, and specific biochemical tests (2) and the availability of an effective therapy, which was first described more than 30 years ago (3) and was approved by the U.S. Food and Drug Administration (FDA) more than 20 years ago. Formation of an Expert Panel and Basis of Recommendations Concerns about misdiagnosis, delayed diagnosis, and inappropriate therapy prompted the American Porphyria Foundation to assemble a panel of experts on the acute porphyrias who were selected on the basis of their clinical and research experience and their contributions to the medical literature. The panel, which represents specialties including internal medicine, pediatrics, genetics, gastroenterology, hepatology, and hematology, was charged with formulating updated recommendations for diagnosing and treating the acute porphyrias. With support from the American Porphyria Foundation, the panel members convened for a day-long meeting to formulate clinical recommendations. Two members, assisted by a medical writer funded by the Foundation, prepared a draft manuscript based on the panels discussion and recommendations. All panel members participated in the review and revision of the manuscript and agreed to the final version. Recommendations are based on the clinical experience of the authors and their review of the literature. Because the acute porphyrias are rare, most of the literature consists of reviews, small series, and case studies. A detailed MEDLINE search on treatment of acute attacks, for example, revealed 71 papers (55 in English and 16 with English abstracts) published between 1966 and October 2004. Of these, 41 were single-case reports, 13 were case series of 10 or fewer patients, and 17 (11 in English) were studies with more than 10 patients (4-20). Altogether, 53 papers discuss more than 1000 patients who received hemin therapy with or without initial treatment with glucose. The American Porphyria Foundation partially funded this review. This nonprofit organization provides information and support to patients with porphyria and their physicians. It receives funding from private sources in addition to a nonrestricted grant from Ovation Pharmaceuticals, the manufacturer of hemin for injection (Panhematin), the only FDA-approved hemin therapy for the acute porphyrias. The Foundation and Ovation Pharmaceuticals had no role in the literature review, the formulation of recommendations, or the drafting and revising of the manuscript. Overview of the Acute Porphyrias Acute Porphyrias Are Inborn Errors of Heme Biosynthesis Each of the acute porphyrias results from the deficient activity of a distinct enzyme in the heme biosynthetic pathway (1). Porphyrias are classified as hepatic or erythroid, depending on whether most of the heme biosynthetic intermediates arise from, and accumulate in, the liver or in developing erythrocytes. They are also classified clinically as acute or cutaneous on the basis of their major clinical manifestations. Of the 5 hepatic porphyrias, 4 characteristically present with acute attacks of neurologic manifestationshence the designation acute porphyrias, a term that does not fully describe the clinical features, which can be prolonged and chronic. Table 1 shows the genetic and enzymatic features of the 4 acute hepatic porphyrias (21): acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare 5-aminolevulinic acid (ALA)dehydratase porphyria. The combined prevalence of these diseases is approximately 5 cases per 100000 persons (1). Numerous mutations have been identified for each disorder. The major manifestations of the acute porphyrias are neurologic, including neuropathic abdominal pain, peripheral neuropathy, and mental disturbances (Table 2) (1, 4, 22-25). These develop during adult life, are more common in women than in men, and are treated by methods to restore heme homeostasis. Variegate porphyria and, much less commonly, hereditary coproporphyria can also cause chronic, blistering lesions on sun-exposed skin that are identical to those in porphyria cutanea tarda, a much more common condition. Photocutaneous lesions may occur without neuropathic manifestations. Table 1. Characteristics of the 4 Acute Porphyrias Table 2. Common Presenting Symptoms and Signs of Acute Porphyria In addition to their highly variable neurologic signs and symptoms, the acute porphyrias are distinct from other porphyrias because of their common overproduction of the porphyrin precursors ALA (an amino acid), and porphobilinogen (a pyrrole). This striking biochemical feature is important for laboratory diagnosis and has implications for pathogenesis of the neurologic manifestations. While porphyrins (tetrapyrroles) are also increased, their measurement is of little value for initial diagnosis because they are also increased (in urine, feces, erythrocytes, or plasma) in other porphyrias and many other medical conditions. Pathogenesis of Acute Attacks The enzyme deficiency in each disorder is partial (approximately 50% of normal in the 3 most common acute porphyrias), and the remaining enzyme activity is usually sufficient for heme homeostasis. Because ALA dehydratase activity normally greatly exceeds that of the other enzymes in the pathway, a more severe deficiency of this enzyme (5% of normal) is required to cause manifestations of ALA-dehydratase porphyria. These enzymatic defects predispose the affected persons to the effects of precipitating factors, including many drugs (for example, barbiturates, anticonvulsants, rifampin, and progestins), endogenous steroid hormones (especially progesterone), fasting, dieting, smoking, and stress from illness, all of which can increase the demand for hepatic heme and induce synthesis of ALA synthase, the first enzyme in the heme biosynthetic pathway. Because hepatic ALA synthase is rate-controlling, production of heme pathway intermediates increases to the point at which the inherited partial enzyme deficiency becomes limiting, and intermediates accumulate in the liver. Porphobilinogen and ALA levels are increased in all patients with acute symptoms of these disorders and in some who are asymptomatic. The cause of hepatic overproduction of porphyrin precursors in the acute porphyrias is better understood than are the mechanisms for neurologic damage. Presumably, symptoms result primarily from the porphyrin precursors themselves rather than a deficiency of heme in nerve tissue (26, 27). Chronic symptoms and signs may reflect previous, unresolved neurologic damage. In the very rare cases of homozygous acute intermittent porphyria (26), variegate porphyria (28), and hereditary coproporphyria (29), severe neurologic manifestations begin in childhood. An allogeneic liver transplantation in a woman with heterozygous acute intermittent porphyria normalized her urinary ALA and porphobilinogen levels in 24 hours and completely eliminated her recurrent neurologic attacks, which supports the hepatic overproduction of porphyrin precursors in causing the neurologic symptoms (27). Si

Hematologic and hepatic manifestations of the cutaneous porphyrias

This chapter has dealt with five photocutaneous forms of human porphyria. The forms are a diverse group of disorders with many different hematologic, hepatologic, and neurologic manifestations. In essence, most photocutaneous porphyrias occurring in childhood will relate to congenital erythropoietic porphyria or protoporphyria. The nature of the skin lesions and a study of the heme precursor profile in red cells, plasma, urine, and feces should easily distinguish these two conditions. CEP is a disease wherein photomutilation is a dominant concern and aggressive new approaches of therapy also have been discussed. In protoporphyria, the dermatologic problem is less severe and the dermatologist should be aware that a subset of patients could develop active liver disease that may lead to fatal cirrhosis. Novel approaches of therapy have been briefly alluded to. With regard to postpubertal photocutaneous porphyria, the classic porphyria cutanea tarda syndrome is associated with liver disease, usually alcoholic with siderosis, and the treatment by phlebotomy to reduce hepatic iron is highly effective. The potential danger of liver carcinoma has been discussed. In subsets of porphyria cutanea tarda, this can be an endemic disease relating to environmental factors, ie, ingestion of polyhalogenated hydrocarbons. The biochemical diagnosis can be attained by fairly straight-forward solvent extraction analyses of urine and feces, showing the dominance of uroporphyrin excretion in the urine and coproporphyrin in the feces. Chromatographic techniques in plasma, bile, and feces reveal a PCT-specific porphyrin: isocoproporphyrin. Rare subtypes with hematologic manifestations, ie, hepatoerythropoietic porphyria and CEP, indicate the wide spectra of disorders that might be associated with a spontaneous deficiency of uroporphyrinogen decarboxylase activity. These latter syndromes are, however, rare. Two hereditary hepatic porphyrias, ie, autosomal dominantly inherited VP and HCP, have been briefly discussed. The hepatic lesion is metabolic, not morphologic, and its expression by the liver relates to its adaptive response to induction of microsomal hemoproteins by a variety of exogeneous and endogeneous compounds, eg, drugs and hormones. Photocutaneous lesions of HCP and VP are identical to PCT, the latter having no neurologic sequelae. In the former two, however, exposure of persons to drugs, such as the hydantoins and barbiturates, can lead to potentially fatal acute porphyric attacks.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Pancreatitis Associated with Interferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

Acute pancreatitis is a rare complication of interferon (IFN) and ribavirin (RBV) therapy. The aimof this study was to determine the incidence, clinical presentation, and outcome of acute pancreatitisin patients with chronic hepatitis C virus (HCV) infection treated with IFN and RBV combinationtherapy. We conducted a retrospective review of 1706 HCV-infected patients treated with IFN α-2band RBV. The diagnosis of drug-induced acute pancreatitis was made based on the presence ofepigastric pain, elevated amylase and lipase levels, and the absence of other identifiable causes ofpancreatitis. Acute pancreatitis was diagnosed in 7 of 1706 HCV-infected patients (0.4%; 95% CI,0.2 to 0.8%) who were treated with IFN α-2b and RBV. The mean age of the patients (four malesand three females) was 51.4 ± 4.7 years and the median duration of therapy prior to developmentof pancreatitis was 12.0 weeks (range, 4.0-21.0 weeks). All patients presented with epigastric painassociated with nausea, vomiting, and/or fever. The median amylase and lipase values at the timeof diagnosis of pancreatitis were 330.0 U/L (range, 182.0-1813.0 U/L) and 500.0 U/L (range,171.0-2778.0 U/L), respectively. IFN and RBV were discontinued in all patients at the time ofdiagnosis and six of the seven patients were hospitalized; one patient refused hospital admission.Pancreatitis resolved in all seven patients and none of these individuals had recurrent pancreatitisduring a median follow-up of 18.0 months (range, 3.0-27.0 months). In conclusion, IFN and RBVcombination therapy is a potential cause of drug-induced pancreatitis in patients with chronic HCV.In these individuals, pancreatitis is often severe enough to warrant hospital admission, althoughsymptoms resolve promptly after discontinuation of antiviral therapy.

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration

Free radical mechanism of oxidation of uroporphyrinogen in the presence of ferrous iron

Human porphyria cutanea tarda is an unusual consequence of common hepatic disorders such as alcoholic liver disease. Hepatic iron plays a key role in the expression of the metabolic lesions, i.e., defective hepatic decarboxylation of porphyrinogens, catalyzed by uroporphyrinogen decarboxylase. This prompted the present study to determine the in vitro effects of iron on the uroporphyrinogen substrate in the absence and presence of atmospheric oxygen. We observed that (i) unless oxygen is the limiting reactant, autoxidation of ferrous iron and iron-catalyzed oxidation of uroporphyrinogen occurred soon after initiating the reaction at pH 7.4 and 30 degrees C in buffers which are non- or poor chelators of iron; (ii) the rates of uroporphyrinogen oxidation were proportional to the initial concentration of ferrous ion; (iii) about 70% of the oxidations of uroporphyrinogen were accountable due to a free-radical chain reaction pathway involving superoxide radical and hence inhibitable by superoxide dismutase; (iv) uroporphyrinogen could be further oxidized to completion by the hydroxyl radical since the reaction was partially inhibited by both mannitol and catalase which prevent hydroxyl radical production; (v) the oxidizing effects of ferric ion on uroporphyrinogen were none or negligible as compared to those of ferrous ion. Ferric was reduced to ferrous ion in the presence of dithiothreitol. When the ferrous ion thus formed was reoxidized in the presence of atmospheric oxygen, minor but definite oxidations of both uroporphyrinogen and dithiothreitol were observed. The oxidations of Fe2+ and uroporphyrinogen could be blocked by 1,10-phenanthroline, a ferrous iron chelator. The data suggest that ferrous is the reactive form of iron that may contribute to pathogenic development of the disease by irreversibly oxidizing the porphyrinogen substrates to nonmetabolizable porphyrins, which accumulate in porphyric liver.

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration. Consensus Interferon Study Group.

OBJECTIVE:The effect of baseline viral concentration on response was assessed as part of a multicenter phase 3 trial evaluating the safety and efficacy of CIFN therapy for chronic HCV infection.METHODS:Patients (n = 472) received either CIFN 9 μg or IFN α-2b 3 MU subcutaneously t.i.w. for 24 wk, followed by 24 wk of observation.RESULTS:Efficacy was assessed by the percentage of patients who achieved normal ALT values or undetectable HCV RNA values (using RT-PCR with a sensitivity of 100 copies/ml). There was a clear relationship between baseline viral concentration and either ALT or HCV RNA response; patients with lower titer HCV RNA had better response rates. End-of-treatment HCV RNA responses were better for patients with low viral concentrations treated with CIFN (51%) than for patients treated with IFN α-2b (31%) (p= 0.03). ALT responses in patients with low viral concentrations were 60% for CIFN-treated patients and 27% for IFN α-2b-treated patients (p < 0.01) at the end of treatment. Patients with high titer HCV RNA were more likely to have a sustained HCV RNA response after treatment with CIFN 9 μg, compared with those treated with IFN α-2b (7%vs 0%, p= 0.03).CONCLUSIONS:Both genotype and baseline viral concentration were independent factors that affected response to interferon.

Roles and pitfalls of transplantation in human porphyria

In this issue of Liver Transplantation, the publication reporting “Liver Transplantation for Erythropoietic Protoporphyria (EPP) Liver Disease” provides important new information. The human porphyrias can be classified by the defective step in heme biosynthesis, by the clinical syndrome such as acute neurovisceral hepatic porphyria, or by the main organ manifesting defective heme biosynthesis.1,2 Using the latter approach, of the seven human porphyrias, two are bone marrow or erythropoietic in origin and the other five, the hepatic porphyrias, reflect the metabolic defect in the liver. Four of the latter can present as acute porphyria and three as photocutaneous diseases. Only Porphyria Cutanea Tarda, often associated with liver damage, e.g., hepatitis C, and iron overload, is purely a cutaneous porphyria with no propensity for an acute attack. Erythropoietic Porphyrias mainly manifest as moderate to severe photocutaneous diseases, and in EPP, hepatobiliary complications, while a particular feature of this porphyria, occur only in a minority of patients. Thus, it is not surprising that the first report of hepatobiliary manifestations came from a dermatologist, Magnus et al. (1961). His group recognized EPP with solar urticaria as a new porphyria syndrome in a 35-year-old restaurateur who had a cholecystectomy 5 years previously for a solitary gallstone.3 Several other investigators reported biliary calculi in EPP at an age younger than expected in cholelithiasis. Protoporphyrin-containing stones were described by Cripps and Scheuer in 1965.4This demonstrated that protoporphyrin in sufficient concentrations derived from the bone marrow but, cleared by the liver, might exceed the ability to be solubilized in biliary micelles to form calculi. If this occurred in bile, what might happen in the liver? The first evidence of hepatic involvement in EPP was reported in 1963 by Redeker et al. (International Porphyria Conference 1963) and confirmed by Cripps and Scheuer in 1965.4 Hepatocyte protoporphyrin in the cytoplasm was confirmed by microfluorospectrophotometry, by dense and irregularly scattered foci of dark brown pigment corresponding to protoporphyrin by fluorescent microscopy,4 and by birefringence in polarized light microscopy.5 Protoporphyrin is hepatotoxic.6–8 Between 1968 and 1980, there were reports of serious hepatic disease with abdominal pain simulating biliary colic and the development of jaundice heralding a relentless downhill fatal course in months.9-11 At laparotomy or autopsy, the livers were black (from protoporphyrin pigment), firm, and nodular. Familial portal fibrosis or cirrhosis has been reported. The metabolic basis for the liver disease in EPP is still an open question. The enzyme defect in EPP is diminished activity of the dimeric inner mitochondrial enzyme, ferrochelatase. This enzyme catalyzes the ultimate stage in heme biosynthesis, which is the insertion of iron into protoporphyrin IX.1 It is an autosomal dominant disease, but with one mutant allele, EPP patients have only 10 to 25% of normal activity.12,13 The mutant enzyme may interfere with the catalytic activity of normal enzyme in the ferrochelatase dimer or the interaction maybe more complex. Ferrochelatase activity is deficient in many tissues studied, including the liver, which may also overproduce protoporphyrin, and the intrahepatic trafficking of protoporphyrin is not known. However, the 65% recurrence of disease post liver transplantation, as reported in this journal, suggests that pigment loading the hepatocytes from the bone marrow protoporphyrin overproduction is the main pathogenetic basis of EPP liver disease. All porphyrins absorb light energy with a major band near 400 nm (the Soret band) and four smaller bands between 500 and 630 nm. Excitation of this pigment by light energy is the basis of photocutaneous porphyria, and longer wave bands have been used therAbbreviations: Epp, erythropoietic protoporphyria; ALA, deltaaminolevulinic acid; PBG, porphobilinogen. From the Center for Liver Disease and Porphyria Research Division of Gastroenterology, U.C. Davis Medical Center, Sacramento, CA. Received September 14, 2005; Accepted September 17, 2005. Address reprint requests to Neville Roy Pimstone, M.D., Center for Liver Disease and Porphyria Research Division of Gastroenterology, U.C. Davis Medical Center, PSSB, Suite 3500, 4150 V Street, Sacramento, CA 95817. Telephone: (916) 734-3751; FAX: (916) 734-7908; E-mail: neville.pimstone@ucdmc.ucdavis.edu Copyright

Uroporphyrinogen decarboxylases from human erythrocytes : purification, complete separation and partial characterization of two isoenzymes

1. Two distinct molecular forms of uroporphyrinogen decarboxylase have been completely separated and highly purified from human erythrocytes. 2. Each protein, with molecular masses of about 52-54 kDa and 35 kDa, are apparently composed of a single polypeptide chain. 3. They may form a functional decarboxylating complex for heme biosynthesis.

A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum α-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential. Cancer Prev Res; 8(9); 864–72. ©2015 AACR.

Current status of medical treatment of gallstones.

Medical dissolution of gallstones is feasible and has worked in clinical practice. Cholelithiasis is both common and a cause of significant morbidity nationally. Thus, to readdress the question posed in the introduction, should there be a more aggressive detection of populations at risk to consider prophylactic or early treatment of gallstones, one has to consider the following. Is it cost effective to treat people with asymptomatic stones when one half of gallstones detected at autopsy have not caused trouble in life? Will the reduction of one health hazard create other hazards, such as colonic cancer? Is it improving the quality of the patients life after successful treatment to have the person return every year for ultrasound or radiologic check-ups for recurrence of gallstones? We feel that despite the low morbidity and mortality of elective surgery, medical dissolution of gallstones is a viable alternative, but, as with most medical decisions, the pros and cons of any therapy for cholelithiasis will ultimately be a decision based on the physician, the patient, and the situation. On the basis of what has been discussed in this review, the approach to treatment should involve a rational understanding of all alternatives.