Heme synthesis - note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)
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Hereditary coproporphyria

The porphyrias are inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors). more...

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Overview

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, and cytochrome.

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. This is, however, not the main problem; most enzymes—even when less functional—have enough residual activity to assist in heme biosynthesis. The largest problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine in which tissue they accumulate, whether they are photosensitive, and how the compound is excreted (in the urine or feces).

Subtypes

There are eight enzymes in the heme biosynthetic pathway: the first and the last three are in the mitochondria, while the other four are in the cytosol.

  1. δ-aminolevulinate (ALA) synthase
  2. δ-aminolevulinate (ALA) dehydratase
  3. hydroxymethylbilane (HMB) synthase
  4. uroporphyrinogen (URO) synthase
  5. uroporphyrinogen (URO) decarboxylase
  6. coproporphyrinogen (COPRO) oxidase
  7. protoporphyrinogen (PROTO) oxidase
  8. ferrochelastase

Hepatic porphyrias

The hepatic porphyrias include:

  • ALA dehydratase deficiency
  • acute intermittent porphyria (AIP): a deficiency in HMB synthase
  • hereditary coproporphyria (HCP): a deficiency in COPRO oxidase
  • variegate porphyria (VP): a deficiency in PROTO oxidase
  • porphyria cutanea tarda (PCT): a deficiency in URO decarboxylase

Erythropoietic porphyria

The erythropoietic porphyrias include:

  • X-linked sideroblastic anemia (XLSA): a deficiency in ALA synthase
  • congenital erythropoietic porphyria (CEP): a deficiency in URO synthase
  • erythropoietic protoporphyria (EPP): a deficiency in ferrochelatase

Porphyria variegata

Variegate porphyria (also porphyria variegata or mixed porphyria) results from a partial deficiency in PROTO oxidase, manifesting itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. It may first occur in the second decade of life; there is a cohort of sufferers living in South Africa descended from a single person from the Netherlands, Berrit Janisz, who emigrated in the 17th century.

Signs and symptoms

The hepatic porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. Cardiac arrhythmias and tachycardia (fast heart rate) may develop as the autonomic nervous system is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation is frequently present, as the nervous system of the gut is affected.

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Pathologic quiz case: A 35-year-old woman with a history of arrhythmia and liver failure
From Archives of Pathology & Laboratory Medicine, 6/1/02 by Mikolaenko, Irina

The patient was a 35-year-old, white woman with a history of rapidly progressive liver cirrhosis diagnosed 1 month before her most recent admission. On this admission, she had signs and symptoms consistent with acute liver failure, hepatic encephalopathy, and recurrent supraventricular tachycardia.

The patient reported a history of tachycardia of unknown origin since the age of 17 years for which she was taking digoxin (Lanoxin). One or 2 years ago bouts of tachycardia became more frequent and atenolol (Tenormin) was added to her drug regimen. Electrocardiogram showed right axis deviation with T-wave inversions in V^sub 1^ through V^sub 3^.

The patient had 3 siblings. Two of her sisters had histories of cardiac arrhythmias. Her younger brother died from a fatal cardiac arrhythmia during a surgical procedure. The patient's medical history was significant for recurrent abdominal pain, which first began at the age of 14 years and had continued since that time. She had been hospitalized on several occasions for the abdominal pain and undergone various surgical procedures to determine the cause of the pain, but to no avail. During the last 12 months, the pain had become severe and sharp in nature. A diagnosis of hereditary coproporphyria was eventually established. She received infusions of glucose and hematin, which gave her symptomatic relief. Her hospital stay was complicated by worsening liver, renal, and respiratory failure with bilateral pulmonary edema and pleural effusions. She died from a fatal cardiac arrhythmia 10 days after the admission.

At autopsy, cardiomegaly with right atrial and ventricular dilation was identified. The thickness of the fatty replacement ranged from 15 (at the basal region) to 8 mm (adjacent to the apex). The right ventricular myocardial wall exhibited a full-thickness replacement of myocardium by mature adipose tissue intermingled with focal bundles of the remaining myocardium (Figure 1). Histologic examination of the right and left ventricles confirmed gross findings. Myocytes persisted only as scattered isolated cells or small strands among the fat cells of the free right ventricular wall (Figure 2). The right ventricle had a thickness of 8 mm and the left ventricle had a thickness of 19 mm. The cut surface of the posterior wall of the left ventricular myocardium exhibited an area of total replacement of the myocardium by adipose tissue (Figure 3).

What is your diagnosis?

Pathologic Diagnosis: Fatty Variant of Arrhythmogenic Right and Left Ventricular Cardiomyopathy Associated With Hereditary Hepatic Coproporphyria

Fatty variant of arrhythmogenic right and left ventricular cardiomyopathy (ARVC) is a familial cardiomyopathy histologically characterized by adipose or fibroadipose replacement of myocytes.

Its prevalence is estimated to be 1 in 5000 people.1 In Italy, it is the most common cause of sudden death in young people. In the United States, it accounts for 17% of all sudden death in young people.2 Autosomal dominant inheritance has been reported in approximately 30% of cases.' In addition, ARVC has a wide genetic, clinical, and histologic spectrum. Although no gene has yet been discovered, several chromosomal loci have been mapped: 14q23, 1q42, 14q12, 2q32, 3p23, 10p12, and 17q21.

It is well recognized that ARVC is a disease with highly variable clinical manifestations, ranging from those that are asymptomatic and slowly progressive to more severe disease presenting with sudden unheralded death in young individuals. Some patients have a normal life expectancy, with the diagnosis being made only post mortem.

The main clinical manifestations of the disease are arrhythmias, complete heart block, heart failure, and sudden death.3 Arrhythmias that characterize ARVC include idiopathic ventricular fibrillation, ventricular extrasystoles, supraventricular tachycardia,4 and ventricular tachycardia of right ventricular origin (with a left bundle branch pattern). The typical electrocardiographic abnormality is T-- wave inversion in leads V^sub 1^ through V^sub 3^.3 The right ventricle is most frequently involved, but left-sided or biventricular cardiac disease also occurs.5 Two pathologic types of ARVC have been proposed: a variant of ARVC characterized exclusively by fat replacement and a variant with fibrofatty replacement of myocytes.

Although extensively discussed in the literature, the origin and natural history of this condition are still unclear.

The polymorphism of this disorder appears to be the result of several basic characteristics of the heart musculature: deposition of fat in the heart musculature, replacement of myocardium by fat, and susceptibility to environmental factors.

Several theories of the origin and pathogenesis of ARVC have been advanced.

According to the diontogenic theory, the absence of myocardium is thought to be the consequence of a congenital aplasia or hypoplasia of the right ventricular wall similar to the parchment heart characterized by gross cardiac structural defect present at birth, which was described by Uhl in 1952. The use of the term arrhythmogenic right ventricular dysplasia (maldevelopment) is in agreement with this theory. It is now recognized that Uhl anomaly and ARVC are 2 separate entities.

Myocellular transdifferentiation can be an alternative mechanism to fatty replacement of lost myocytes in the pathogenesis of ARVC. Gene defect mapped to chromosome 14q23-q246 favors genetically determined atrophy similar to the one that is well described in the skeletal muscle of patients with Duchenne and Becker diseases. The 14q-q24 region includes the genes of Beta-spectrin and alphaactinin. The similarity between the myocardial dystrophy observed in ARVC and the skeletal muscular dystrophy observed in Duchenne and Becker diseases and the structural homology between the alpha-actinin gene and the aminoterminal domain of dystrophin are all highly suggestive of a defective alpha-actinin gene. If this theory proves to be true, then the term arrhythmogenic right ventricular dystrophy might appear the most appropriate.

In the inflammatory theory, the fibrofatty replacement is regarded as a consequence of reparative process in the setting of chronic myocarditis. A genetic predisposition to viral infection eliciting immune reactions cannot be excluded. The finding of lymphocytic infiltrates has led to the consideration of ARVC as a chronic myocarditis. Various infectious agents, such as Tryponosoma cruzi, rubella virus, and mycoplasma, have been related to ARVC. Coxsackie virus genome in the myocardium of patients with ARVC was identified using reverse transcriptase-nested polymerase chain reaction protocol and nucleic acid sequencing.7

In the degenerative theory, the loss of myocytes is considered to be a result of progressive myocyte loss due to some metabolic or ultrastructural defect, resulting in substitution of degenerated myocytes by fat.

It was recently suggested that myocardial cell death in ARVC could represent a programmed cell death known as apoptosis.8

Clinical diagnosis can be established based on the presence of minor and major criteria encompassing structural, functional, histologic, cardiographic, and genetic factors according to the International Society and Federation of Cardiology.

References

1. Thiene G, Basso C, Danieli G, Rampazzo A, Corrado D, Nava A. Arrhythmogenic right ventricular cardiomyopathy. Trends Cardiovasc Med. 1997;7:8490.

2. Chen WK, Edwards WD, Hummill SC, Bailey KR, Ballard DJ, Gersh BJ. Sudden unexpected non-traumatic death in 54 young adults: a 30-year population-based study. Am J Cardiol. 1995;76:148-152.

3. Kullo Ii, Edwards WD, Seward 113. Right ventricular dysplasia: the Mayo Clinic experience. Mayo Clin Proc. 1995;70:541-548.

4. Tone IL, Castro-Miranda R, Iwa T, Poulain F, Frank R, Fontaine GH. Frequency of supraventricular tachyarrhythmias in arrhythmogenic right ventricular dysplasia. Am J Cardiol. 1991;67:1153.

5. Pinamonti B, Pagnan L, Bussani R, Ricci C, Silvestri F, Camerini F. Right ventricular dysplasia with biventricular involvement. Circulation. 1998;98:19431945.

6. Rampazzo A, Nava A, Danieli C, et al. The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24. Hum Mol Genet. 1994;3:2151-2154.

7. Grumbach IM, Vonhof S, Stille-Siegener M, et al. Coxsackievirus genome in myocardium of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Cardiology. 1998;89:241-245.

8. Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N EnglJ Med. 1996; 335:1190-1195.

Irina Mikolaenko, MD; Micheal G. Conner, MD

Accepted for publication September 10, 2001.

From the Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, Ala.

Corresponding author: Michael G. Conner, MD, Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, 506 Krake Bldg, 619 S 19th St, Birmingham, AL 35233-6823 (e-mail: mgconner@path.uab.edu).

Copyright College of American Pathologists Jun 2002
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