Page 929 - Williams Hematology ( PDFDrive )

904 Part VI: The Erythrocyte Chapter 58: The Porphyrias 905

measurement is useful for screening of asymptomatic family members aching, malaise, hemolysis, anaphylaxis, and circulatory collapse. 240,241
if a known case in the family has low erythrocyte enzyme activity, but Excessive dosing caused reversible acute renal tubular damage in one
is less dependable than DNA testing. PBGD deficiency can be docu- case. 242
mented in the fetus by measuring the enzyme activity or by identify- Controlled trials comparing initial treatment with either glu-
ing the maternal or paternal mutation in amniotic fluid cells. However, cose or hemin are lacking, except for one randomized, double-blind,
prenatal diagnosis is usually not indicated because the great majority of placebo-controlled trial of heme arginate for acute attacks of porphy-
heterozygous carriers of PBGD mutations have a good prognosis. ria, which was underpowered (only 12 patients). Although treatment
with hemin was delayed for 2 days, striking decreases in urinary PBG
Therapy and trends in clinical benefit were noted. In contrast, a larger uncon-
243
Hospitalization is usually required for treatment of attacks, although trolled study enrolled 22 patients who had 51 acute attacks, and heme
well-characterized patients with frequently recurring attacks that arginate was initiated within 24 hours of admission in 37 attacks (73
respond rapidly to treatment are sometimes managed as outpatients. percent); all patients responded and hospitalization was less than 7 days
235
Hospitalization facilitates treatment of severe symptoms, intravenous in 90 percent of cases. Therefore, based on this and numerous other
therapies and monitoring of respiration, electrolytes and nutritional uncontrolled clinical studies, it is now recommended that most acute
status. Admission to intensive care is warranted if the vital capacity is attacks of porphyria be treated promptly with intravenous hemin, with-
impaired. Harmful drugs should be discontinued whenever possible. out an initial trial of intravenous glucose. 235,243a Response to hemin may
Pain, nausea, and vomiting are generally severe and require narcotic be delayed or incomplete when there is advanced neurologic damage.
analgesics, chlorpromazine or another phenothiazine, or ondansetron. Subacute or chronic symptoms are unlikely to respond.
Low doses of short-acting benzodiazepines are probably safe for anxiety Liver Transplantation Liver transplantation has been highly effec-
190
and insomnia. β-Adrenergic blocking agents may be useful to control tive in several patients who were disabled by recurrent attacks of AIP.
tachycardia and hypertension, but may be hazardous in patients with This may be an option for severely affected patients.
hypovolemia or incipient cardiac failure. Seizures are treated by cor- Other Therapies Cimetidine has been recommended for human
231
recting hyponatremia, if present. Almost all anticonvulsant drugs have acute porphyrias based on uncontrolled observations in small num-
at least some potential for exacerbating acute porphyrias. Clonazepam bers of patients. 244,245 This drug inhibits hepatic CYPs, and can prevent
may be less harmful than phenytoin, barbiturates, or valproic acid. 232,233 experimental forms of porphyria induced by agents such as allylisopro-
246
Bromides, gabapentin, and vigabatrin are safe. pylacetamide that undergo activation by these enzymes. However,
Carbohydrate Loading Glucose and other carbohydrates repress these mechanisms are not immediately relevant to inherited porphyrias
hepatic ALAS1 and reduce porphyrin precursor excretion, but the in humans. Therefore, cimetidine cannot be recommended as an alter-
effects are weak compared to those of hemin. Attacks with mild pain and native to hemin.
without severe manifestations such as paresis and hyponatremia may be Prevention of Acute Attacks Multiple inciting factors must be
treated with carbohydrate loading. Oral glucose polymer solutions may avoided especially in patients who continue to have repeated attacks.
be given if tolerated. Intravenous treatment with 300 to 500 g of intra- Consultation with a dietitian may be useful to identify dietary indis-
venous glucose, usually administered as a 10 percent solution, is recom- cretions, and to help maintain a well-balanced diet somewhat high in
mended. However, the dilutional effects of a large volume of free water carbohydrate (60 to 70 percent of total calories). There is little evidence
may increase risk of hyponatremia. A more complete parenteral nutri- that additional dietary carbohydrate helps further in preventing attacks.
tion regimen may be needed if oral or enteral feeding is not possible. Iron deficiency, if present, should be corrected. Patients who wish to
Intravenous Hemin Hemin is much more potent in reducing lose excess weight should do so gradually and when they are clinically
levels of ALA and PBG compared to glucose. Although controlled stable.
clinical trials are lacking for all current therapies for acute attacks of Gonadotropin-releasing hormone analogues can prevent repeated
porphyria, consensus recommendations are that the clinical benefits of attacks that are confined to the luteal phase of the menstrual cycle, 247,248
hemin are superior to other available therapies. 234,235,243a Hemin is avail- but are less effective in patients with attacks partially associated with the
able in the United States as a lyophilized hematin preparation (Panhe- cycle. If treatment is effective after several months, low-dose estradiol,
matin, Recordati Rare Diseases, Northfield, IL), and was the first drug preferably by the transdermal route, or a bisphosphonate may be added
approved under the Orphan Drug Act. Heme arginate (Normosang, to prevent bone loss and other side effects, or treatment changed to a
Orphan Europe, Paris, France), which is a stable preparation of heme low-dose oral contraceptive. Hemin administered once or twice weekly
and arginine, is available in Europe and South Africa. 235,236 Hemin, when can prevent frequent, noncyclic attacks of porphyria in some patients. 249
infused intravenously as hematin or heme arginate, becomes bound to Long-Term Monitoring Patients with acute porphyrias are at risk
circulating hemopexin and albumin and is then taken up primarily by for renal damage and hepatocellular carcinoma. Renal function should
hepatocytes. It then enters and reconstitutes the regulatory heme pool be monitored, hypertension controlled, and nephrotoxic drugs avoided.
and represses the synthesis of hepatic ALAS1. This results in a dramatic Current recommendations are that patients with acute porphyrias who
reduction in porphyrin precursor excretion. The standard regimen for are older than age 50 years, and especially those with continued eleva-
treatment of acute attacks is 3 to 4 mg/kg daily for 4 days. Treatment tions of ALA and PBG, be screened at least annually by ultrasonogram
may be extended if a response is not observed within this time. Hemin or an alternative imaging method to detect hepatocellular carcinoma at
has been administered safely during pregnancy. 235,236,243a an early stage. 243a
Product labeling recommends reconstitution of hematin with ster-
ile water. But it was subsequently discovered that degradation products HEREDITARY COPROPORPHYRIA AND
of hematin begin to form immediately upon reconstitution with water,
and these are responsible for phlebitis at the site of infusion, which VARIEGATE PORPHYRIA
occurs frequently and can lead to loss of venous access with repeated Definition
dosing, and a transient anticoagulant effect. 236a Stabilization of hema- These closely related hepatic porphyrias are caused by deficiencies of
tin with 25 percent human albumin can prevent these adverse effects, CPO and PPO, the sixth and seventh enzymes of the heme biosynthetic
238
239
and is currently recommended. Uncommon side effects include fever, pathway. They present with neurovisceral symptoms, as in AIP, or with

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