Vascular Involvement in Primary Hyperoxalosis: An Evidence Based Sytematic Overview Over a Fifty Year Span

Article Information:


Group: Volume 02
Subgroup: Issue 03
Date: January 2010
Type: Review Article
Start Page: 390
End Page: 396

Authors:

  • Farouk Mookadam
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Mohammed El Kheir
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Mohsen Alharthi
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Sherif Moustafa
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Franci J Kazmier
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Robert McBain
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Martina Mookadam
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Jamil Tajik
  • Department of Cardiovascular diseases, Mayo Clinic College of Medicine, Arizona, USA
  • Dawn S Milliner
  • Division of Nephrology, Mayo Clinic Hyperoxaluria Center, Mayo Clinic College of Medicine, Rochester, Minn, USA

      Correspondence:

      Affiliation: Department of Cardiovascular diseases, Mayo Clinic College of Medicine
      City, Province: Arizona,
      Country: USA
      Tel: 480-301-4012
      Fax: 480-301-8018
      E-mail: mookadam.farouk@mayo.edu

Abstract:


Background and Aims: Primary hyperoxaluria (PH) is a rare genetic disorder characterized by calcium oxalate nephrocalcinosis leading to renal failure. When renal function is impaired, plasma oxalate concen-tration increases and extra-renal oxalate deposition occurs. Vascular involvement includes vasculitis and ischemic related morbidity and death. The prevalence of vascular involvement is not known with only a few cases described in the literature. A systematic overview of the literature was performed to identify the demographics, clinical presentation and outcomes of such patients.

Methods: A computerized search of MEDLINE (Jan 1950 to May 30, 2007), EMBASE (Jan 1988 to May 2007) and CINAHL (Jan 1982 to May 30, 2007 identified twenty three cases of vascular involvement.

Results: The majority of those reported in the literature are young females (74%). Vascular deposition of oxalate crystals presents as skin vasculitis; limb or mesenteric ischemia or gangrene. Stroke is uncommon.

The lower limbs are affected more than upper limbs followed by mesenteric vessels. Vasculitic skin manifes-tations occur in 52% of cases. Death occurred in 8 (38%) of cases (63% abdominal gangrene/sepsis; 37% cardiac).

Conclusions: Little information exists on vascular involvement in PH. Morbidity and mortality is high (death and limb loss occurring in 2/3 of patients). Awareness of the vascular presentation is thus important to allow a better understanding. Prospective reporting via a national or international registry on optimal management of vascular involvement in PH is needed.

Keywords: Nephrocalcinosis, Urolithiasis, Aminotransferase, Vasculitis, Vasculopathy, Skin Rash, Amputa-tion, Gangrene, Hepatorenal Transplant.

Manuscript Body:


Introduction

Primary hyperoxaluria (PH) is a rare genetic disor-der characterized by calcium oxalate nephrolithiasis and nephrocalcinosis leading to renal failure, often with extrarenal oxalate deposition or systemic oxalo-sis. PH was first described by Lepoutre in 1925, but the first intra vitam diagnosis was in 1953 (1, 2). PH subtypes 1 and 2 are inherited as an autosomal reces-sive disorder.

PH type 1 (PH1), the most common type of PH, is caused by a deficiency of the peroxisomal liver enzyme alanine glycosylate aminotransferase (AGT) which normally converts glyoxylate to glycine (3-5).

This defect results in an increased glyoxylate pool which leads to increased synthesis of poorly soluble oxalate (6). Oxalate overproduction coupled with renal excretion results in marked hyperoxaluria with nephrocalcinosis and recurrent urolithiasis. Most patients experience repeated episodes of urolithiasis in childhood, some develop renal failure as early as infancy, while others first present as adults with symptomatic urolithiasis (7).

PH type 2 (PH2), a less common form of PH, re-sults from a deficiency in the cytosolic enzyme gly-

oxylate reductase. This enzyme is expressed in many cells including hepatocytes, renal parenchymal cells, fibroblasts, and lymphocytes. Glyoxylate reductase is responsible for the conversion of glyoxylate to glycolate. This defect similar to PH1, results in an increased glyoxylate pool which leads to increased synthesis of poorly soluble oxalate (8).

Non type 1, non type 2 PH is currently used to describe a heterogeneous group of not other wise six articles were identified. Seventeen articles were deemed relevant (i.e. they have vascular involvement directly due to primary hyperoxaluria). Twenty three patients with primary hyperoxaluria and vascular involved were identified. The bibliographies of all relevant articles were also searched for new cases.

End points

The end points include any form of vasculopathy or vasculitis including any vascular bed as well as skin vasculitis, ulcerations, limb gangrene and or amputa-tion, death and stroke. Radiological, histopathological biopsy or post surgical tissue diagnoses were consid-ered confirmatory.specified zariants of PH, extrarenal deposition of oxalate occurs in bone, retina, arterial media, nerves, skin, and myocardium (8-15). Symp-toms of systemic oxalosis in patients with PH1 are often ameliorated or corrected with combined hepato-renal transplant, which is considered curative therapy. Vascular manifestations can result in vas- culitis or significant ischemic related morbidity and death. The true prevalence of vascular involvement is not known with few cases in the literature. The aim of this paper is to perform a systematic overview of all published reports on vascular manifestations of PH and to describe the demographics, clinical presentation, diagnosis, treatment and outcomes of this group of patients.

Materials and Methods

A computerized search of OVID MEDLINE (Jan1950 to May 30, 2007), EMBASE (Jan 1988 to May 2007) and CINHAL (Jan 1982 to May 30, 2007) was performed. The following search terms were used to identify English language studies: ‘Primary hyperoxaluria vasculitis'; ‘primary hyperoxalosis and vasculitis'; ‘Primary hyperoxaluria, vascular disease'; Primary hyperoxaluria, vascular involve- ment. Sixty

Statistical analysis

Age and gender were expressed as means and standard deviations Groups by gender and organ involved were compared by the absolute number of cases (n) and percentages (%) of the total reported cases included in the study.

Results

Twenty three patients with vascular complications of systemic oxalosis were identified. Clinical infor-mation is summarized in table 1 and distribution of the vascular lesions in table 2. Of the twenty three patients, mean age was 34±13, 17 (74%) were female.

 

Table 1. Studies of vascular involvement including demographics, clinical presentation and outcomes in PH

 

Case

 

Age/ Sex

Presentation

Diagnostic Tool

Treatment

Vessels

Outcome

Christopher J/2004 

25

F

Bilateral foot pain + skin discoloration

CT Angio  

Distal to popliteals/ superior mesenteric art    

Cyclophos- phamide + prednisone+ CCB

Death of cardiac

complications

Vincent M/2002

40

F

S/C painful nodules on left arm & bilateral lower limbs

Skin biopsy

?

?

prepared for transplant

 

Herrmann G/ 2004

49

F

dermal plaques on both thighs

Skin biopsy

?

UV A1 therapy+ oral Oxf

slight improvement

Somach/1995

38

F

painful eruptions on lower limbs

Skin biopsy

?

?

death of sepsis

Shih /2000

39

F

purpura on both upper and lower limbs

Liver biopsy

?

fentanyl patches+ mupirocin oint

toes amputation

Jonshon J /2000

49

F

pain in both feet

Kidney biopsy

calf vessels/ small intestinal  

prostsacyclin infusion

death of acute abdomen

O Reilly/2001

25

F

necrotic lesions on the extremities

CT Angio + skin biopsy

extremity vessels    

cyclophosphamide + prednisone    

death of cardiac complications

Damme- /

16

F

claudication + skin discoloration

Kidney biopsy 

femoral & popliteal   

Na nitroprusside + excess Mg   

improved, disappeared after renal transplant

Arbus/1974

10

F

gangrene in all extremities

CT Angio & X-Rays    

arteries of legs

epidural anesthesia & hyperbaric O2  

Death

Blackburn/1975

18

F

gangrene

CT Angio

Femoral + hypogastric

?

Death

Boquist et al /1973

44

M

ischemic changes in arms & legs 

?

?

?

Death

Vanrenter- ghem/1984

54

M

progressive vascular lesions

?

?

?

amputation of both legs and one arm

Riksen /2002

51

M

progressive claudication

Kidney biopsy

distal art of LL

IV steroids

?

Marc F/1986

27

M

ischemic changes of left LL

CT Angio

LL vessels

?

below knee amputation

Candido/2004 

18

F

paresthesia & cold lower limbs 

Echo- Doppler   

right ant tibial, pulmonary, & cerebral micro- circulation 

vasodilators 

partial response to treatment

Suneet /1999

54

F

livedo reticularis

Liver biopsy

?

Steroids

symptoms improved

Bastani/1999

23

F

livedo reticularis

Skin biopsy

?

?

improved after liver transplant

Melissa/2004

30

F

livedo reticularis + ulcers on legs

Renal + skin biopsy

?

enzymatic debridments

death of cardiac complications

John /1997

22

F

livedo reticularis in lower limbs

Skin biopsy + echo

?

?

improvement after 2nd renal transplant

Jansen /1974

27

F

spasms of hands + facial paresthesias

CT Angio & skin biopsy

left internal & external carotids

?

right leg amputation

Jansen /1974

42

F

progressive renal function impairment

Renal, skin, arterial biopsy

?

?

?

Freiberg / 1993

38

M

worsening  digital pain

hand X-ray

?

CCB & digital sympathectomy

Fing er and toes amputation

Freiberg / 1993

35

M

muscle weakness & white tissue deposits on both hands

?

?

?

?

 

PH, primary hyperoxaluria; CT, Computerized Tomography; ?, no data available

Diagnostic modalities

All twenty three cases reported clinical manifesta-tions suggestive of vascular involvement due to PH. More than half of the reported cases 14 (61%) were diagnosed by biopsy (skin-9=39%, kidney-5=22%, liver-2=9%, arterial-1=4%). It should be noted that patients with calciphylaxis can present with livedo reticularis, therefore skin biopsy is necessary toa skin rash, 12 (52%) with livedo (11 with livedo reticularis and only one case with livedo racemosa) and 4 (17%) with skin ulceration, Vasculitis in as-sociation with limb ischemia occurred in all 23 cases (100%).

Ischemic Limb

Limb ischemia was more common in the lower limbs affecting 21 (91%) patients. Single limb vas-culitis occurred in 1 (4%), 2 limb ischemia in 12 (52%), 3 limb ischemia in 3(13%). Seven (30%) pa-tients had both upper and lower limb involvement.

Bowel Ischemia

The third commonest manifestation of vasculitis  presented with bowel ischemia in 3 (13%) and frank gangrene was present in 3 (13%). Overall mortality in this group was 8 (38%). In the 3 (13) patients with bowel ischemia mortality was 100%.

Other vasculopathy

There was only one case (4%) each of ca- rotid arteryand one case (4%) intracerebral artery involvement.

 

Table 2. Patient demographics, clinical presentation and outcomes

 

 

No. (%) of patients

AGE, range (mean ± SD)

10-54 (34 ± 13) years

GENDER

 

Male

6 (26)

Female

17 (74)

CLINICAL PRESENTATION

 

Livedo

12 (52)

gangrene

3 (13)

Cutaneous ulcers?

4 (17)

Abdominal pain

2 (9)

stroke

2 (9)

Limb: Upper vs lower

9 (39) vs 21 (91)

Mesenteric vessels

3 (13)

Carotids

1 (4)

Cerebral

1 (4)

Vascular Studies

 

Biopsy

14 (61)

CT angiography

Ultrasound

MRA

6 (26)

2 (9)

1 (4)

 

Other vasculopathy

There was only one case (4%) each of ca-rotid arteryand one case (4%) intracerebral artery involvement.

Management

Medical management of these patients included hyperbaric oxygen and immunosuppressive therapy with cyclophosphamide and steroids in 4 (17%) while vasodilators such as calcium channel blockers and magnesium were used in 5 (22%) and UV A1 therapy in one case (4%). Significant improvement in vascular manifestations was reported in 3 (13%) cases that underwent hepatorenal transplant. In the cohort of limb ischemia amputations were necessary in 6/21 (29%) patients. Bowel resection was done in one patient who died two days later.

Discussion

The primary hyperoxalurias are a group of rare autosomal recessive metabolic disorders that lead to an accumulation of oxalate in the body (16). Early in the course of the disease, calcium oxalate deposits are confined to the kidneys where oxalate clearance usually takes place. Once significant renal insuf-ficiency develops, the kidneys are no longer able to excrete the large excess of oxalate produced.

On histologic examination of the blood vessels in these reports, the deposits were limited to the vessel wall, with arterial and arteriolar involvement being more common than venous involvement in most of the cases (17). Crystal deposition in the tunica media of arteries leads to subintimal fibrosis followed by ar-teriolar occlusion and occasional thrombosis (16). The vascular obliteration accounts for livedo reticularis and ischemia to tissues (16). Livedo is the common-est presentation of vascular involvement in patients with primary hyperoxaluria 12 (52%). Deposits of calcium oxalate in the superficial arterioles leads to cutaneous ischemia subsequently leading to the live- doid pattern (16). Thus the development of livedo reticularis in a patient on dialysis should raise the suspicion of the possibility that PH may be cause of end stage renal disease (15). All cases included in our study showed signs of limb ischemia with the lower limbs being affected in the majority of 21 (91%) and 7 (30%) had all upper and lower limbs involvement. Only one case (4%) showed single limb ischemia. Three cases (13%) had mesenteric vessels affected with 100% mortality.

Treatment was mentioned in about half the reports. Five (22%) were treated with vasodilators such as calcium channel blockers, magnesium, and Na nitroprusside. Four of them (17%) were given immunosuppressives such as cyclophosphamide and steroids on the basis that this was a vasculitis with an inflammatory reponse. Furthermore UV A1 therapy was used in a single case as was hyperbaric O2. No single treatment used showed significant improve- ment in the patient's symptoms. Three cases reported significant improvement in the vascular manifesta- tions after combined hepato-renal transplant (14), one patient developed vascular involvement after hepato-renal transplantation (9, 14).

Taking into consideration the age at which some of the cases included in our study were reported, the mortality rate was high at 38% (8 cases). Three patients died of cardiac complications and three of sepsis. Cause of death was unspecified in the 2 remaining cases. Of the twenty three cases three patients also had retinal oxalate deposition, three cases showed bone deposits, and one patient had both pancreatic and gall bladder involvement from primary hyperoxaluria.

Conclusions

Little information exists on vascular involvement PH. Among published reports whose disease pro- gressed to renal failure, and who developed vascular oxalosis, morbidity and mortality appears high (death and limb loss occurring in 2/3 of patients). The ma- jority are young females (74%). Vascular deposition of oxalate crystals presents as skin vasculitis, cutane-ous ulcers, limb or mesenteric ischemia or gangrene. The lower limbs are affected more frequently than the upper limbs followed by the mesenteric vessels.

Vasculitic skin manifestations occur in 52% of cases. Systemic oxalosis in patients with vascular involve-ment is often fatal (death in 38%). The most sensi-tive tools for assessing vascular involvement are the clinical examination, non-contrast CT imaging and computerized tomographic angiography in addition to skin biopsy. Although several types of treatments were attempted, none was of clear benefit. The opti-mal management appears to be early recognition of the disease, followed by avoidance of high serum oxalate levels by frequent dialysis and early curative dual organ hepato-renal transplantation. In cases where serum oxalate levels are high or vascular in-volvement established at the time of transplantation, then post transplant dialysis to remove as much of the serum oxalate as possible may be beneficial.

Prospective reporting on vascular manifestations via a national/ international registry is important to allow a better understanding of the frequency, complications and optimal management of vascular involvement in the primary hyperoxalurias.

Acknowledgements

This work was supported by funding from the Oxalosis and Hyperoxaluria Foundation and the NIDDK (RO1 DK073354)

Conflict of Interest

None declared.

References: (17)

  1. Parr C, Miller F, Gregory M, Yoon H. SIR 2004 Film Panel Case: Primary Hyperoxaluria Type I Mimicking Arterial Vasculitis--A Lethal Disease. Journal of Vascular and Interventional Radiology. 2004;15:1017-20.
  2. Jansen LH, Groeneveld JL, Van Der Meer JB. Deposition of calcium oxalate in the skin in two patients suffering from oxalosis caused by primary hyperoxaluria. Arch Dermatol Forsch. 1974;250:323-50.
  3. Herrmann G, Krieg T, Weber M, Sidhu H, Hoppe B. Unusual painful sclerotic plaques on the legs of a patient with late diagnosis of primary hyperoxaluria type I. The British journal of dermatology. 2004;151:1104.
  4. Somach SC, Davis BR, Paras FA, Petrelli M, Behmer ME. Fatal cutaneous necrosis mimicking calciphylaxis in a patient with type 1 primary hyperoxaluria. Arch Dermatol.1995;131:821-3.
  5. Shih HA, Kao DM, Elenitsas R, Leyden JJ. Livedo reticularis, ulcers, and peripheral gangrene: cutaneous manifestations of primary hyperoxaluria. Arch Dermatol.2000;136:1272-4.
  6. O'Reilly MA, Meadows KP, Egan CA. Off-center fold:necrotizing livedo reticularis. Diagnosis: primary hyperoxaluriatype I. Arch Dermatol. 2001;137:957-62.
  7. Freiberg AA, Fish DN, Louis DS. Hand manifestations of oxalosis. J Hand Surg Am. 1993;18:140-2.
  8. van Damme-Lombaerts R, Proesmans W, Alexandre G, van Dyck M, Serrus M, Wilms G. Reversible arterial spasm in an adolescent with primary oxalosis. Clin Nephrol.1988;30:235-8.
  9. Riksen NP, Timmers HJ, Assmann KJ, Huysmans FT.Renal graft failure due to type 1 primary hyperoxaluria.Neth J Med. 2002;60:407-10.
  10. Glickstein MF, Haggar AM, Coleman BG. Vascular and soft tissue calcification in systemic oxalosis: CT diagnosis. J Comput Assist Tomogr. 1986;10:691-3.
  11. Diaz C, Catalinas FG, de Alvaro F, Torre A, Sanchez C, Costero O. Long daily hemodialysis sessions correct systemic complications of oxalosis prior to combined liver-kidney transplantation: case report. Ther Apher Dial.2004;8:52-5.
  12. Singh S, Tai C, Ganz G, et al. Steroid-responsive pleuropericarditis and livedo reticularis in an unusual case of adult-onset primary hyperoxaluria. Am J Kidney Dis. 1999;33:e5.
  13. Bastani B, Mistry BM, Nahass GT, Joh J, Dundoo G, Solomon H. Oxalate kinetics and reversal of the complications after orthotopic liver transplantation in a patient with primary hyperoxalosis type 1 awaiting renal transplantation.Am J Nephrol. 1999;19:64-9.
  14. Rubenstein MC, Martinelli PT, Bayer-Garner IB, Klebuc MJ, Curry JL, Hsu S. Persistent cutaneous manifestationsof hyperoxaluria after combined hepatorenal transplantation.Dermatol Online J. 2004;10:10.
  15. Farreli J, Shoemaker JD, Otti T, et al. Primary hyperoxaluria in an adult with renal failure, livedo reticularis, retinopathy, and peripheral neuropathy. Am J Kidney Dis.1997;29:947-52.
  16. Marconi V, Mofid MZ, McCall C, Eckman I, Nousari HC. Primary hyperoxaluria: report of a patient with livedo reticularis and digital infarcts. J Am Acad Dermatol.2002;46:S16-8.
  17. Johnson JS, Short AK, Hutchison A, Parrott NR, RobertsIS. Small intestinal infarction: a fatal complication of systemic oxalosis. J Clin Pathol. 2000;53:720-1.