metabolic bone disease (anticonvulsant osteomalacia) and ......case report metabolic bone disease...

CASE REPORT

Metabolic Bone Disease (Anticonvulsant Osteomalacia) andRenal Tubular Acidosis in Tuberous Sclerosis

Janos P. Rado and Agnes Haris

The characteristics triad of tuberous sclerosis-adenoma sebaceum, mental deficiency andepilepsy-associated with distal-type renal tubular acidosis was combinedwith anticonvulsantosteomalacia in a 41-year-old woman.In addition to the specific bone lesions of tuberous sclerosis,

the bone disease was caused by an adverse effect ofa drug and possibly also by the renal disorderleading to significant musculoskeletal disability. In response to calcium carbonicum and 1-25-dihydroxyvitamin D therapy the musculoskeletal disability healed and the abnormal biochemicalmarkers of anticonvulsant osteomalacia disappeared. The present observation draws attention to

the increased hazard threatening patients on chronic anticonvulsant therapy simultaneouslysuffering from renal diseases.(Internal Medicine 32: 574-579, 1993)

Key words: tuberous sclerosis, epilepsy, renal tubular acidosis, hypocalcemia, D hypovitaminosis,anticonvulsant osteomalacia

Introduction

Tuberous sclerosis is a rare familial disease with a defect inthe development of ectodermal structures (1-4). Although it istransmitted by autosomal dominant inheritance, about 80 percent of the cases are sporadic, due to newmutations. The typicalclinical triad of the disease consists of mental deficiency,epilepsy, and a characteristic, papular, salmon colored erup-tion, distributed in a butterfly pattern on the face, known asadenoma sebaceum. There may be visceral lesions, includingmost commonly,multiple angiomyolipomasof the kidneys,rhabdomyomasof the heart, tumorous malformations of theliver and adrenal glands, cystic transformation of the lungs andretinal hamartomas. The most commoncause of death is renaldisease - on the basis of the 355 patients examined at the MayoClinic (4). In the brain there are multiple "tubers" whichdevelop from abnormal glial cells, neuron proliferation anddeposition of calcium. The sclerotic lesions in the bones,

hypopigmented spots over the trunk and limbs , ungual fibromasand the so-called Koenen's tumors of the gingiva are alsocharacteristic of this disease (1-4).The purpose of this paper is to present a patient, in whomthespecific bone lesions of tuberous sclerosis were combinedwithdrug-induced osteomalacia. In addition the bone disease wasprobably enhanced by the influence of concurrent renal tubularacidosis. Our observations suggest that clinicians should beaware of the increased risk of anticonvulsant osteomalacia

threatening patients on chronic antiepileptic therapy sufferingsimultaneously from renal diseases.

Case ReportA 41-year-old womanwas admitted to the hospital onOctober 2, 1990, because of lower back pain, increasing mus-cular weakness and bone tenderness in her lower extremities.The first seizures of epilepsy occurred at the age of three, andlater, on the basis of findings of adenomasebaceum, mildmental retardation and specific bone lesions, tuberous sclerosiswas diagnosed. No history suggesting a disorder of tuberoussclerosis was found in the patient's relatives. She had beentreated with anticonvulsants since her childhood. The treatmentincluded first phenacemid, afterwards she took 2x250 mgprimidone and 2x 1 00 mg phenytoin daily. No epileptic seizureshad occurred for the last 20 years. She had undergone cosmeticsurgery three times due to adenomasebaceumlesions on herface (Fig. 1). She was followed regularly in the nephrologicoutpatient clinic because of her proteinuria. In the last year 80mg ofpropranolol was administered daily due to her high bloodpressure.The physical examination revealed yellow-brownish papulareruption distributed in a butterfly pattern over the face (Fig. 1 ),hypopigmented spots of the skin over the lower part of the back,and an ungual fibroma on the right hallux (Fig. 2). Her bloodpressure was 190/100 mmHgand pulse rate was 72/min. No

From the Department of Medicine, Nephrology and Hypertension, Uzsoki Hospital, BudapestReceived for publication March 8, 1993; Accepted for publication June 17, 1993Reprint requests should be addressed to Dr. Janos P. Rado, Department of Medicine, Nephrology and Hypertension, Uzsoki Hospital, Uzsoki Street 29, Budapest

1426 Pf. 6, Hungary

574 Internal Medicine Vol. 32, No. 7 (July 1993)

Osteomalacia, RTAand Tuberous Sclerosis

å

; ** .*.

Fig. 1. Face of the patient (after several cosmetic surgical interventions):typical "adenomasebaceum".

abnormality was found in the chest or abdomen. In the lowerextremities, especially proximally, the patient showed muscu-lar atrophy and bone tenderness. An electrocardiogram demon-strated sinus rhythm, left anterior hemiblock, the PQ was 0.20sec, and the QT was 0.44 sec at a rate of72. Laboratory data onadmission are shown in Tables 1 and 2.Bicarbonate loading tests. After intravenous infusion of 1 00mmolNaHCO3,a significant amount of bicarbonate could bedetected in the urine, without normalization of the acid bloodpH value. The difference in pCO2 between urine and blood waszero suggesting the distal type renal tubular acidosis (6) (Fig. 3).The same findings were obtained in the repeat bicarbonateloading tests carried out during the course of 1-25-

dihydroxyvitamin D therapy. [The method of the bicarbonateloading test, illustrated in Fig. 3, is as follows: 100 mmol 4.2%NaHCO3solution was infused intravenously over 1 20 minutes.The determinations of blood and urine gases were performedbefore the test and at the end of every hour for four hours. Sincethe blood pH was still acidotic 60 minutes after completion ofthe infusion, more bicarbonate (67 mmol) was administeredorally.]

Chest film showed slight cardiac enlargement. Dorsal andlumbar spine radiography detected loss of bone density of thevertebral bodies with thinning and relative increase in density

Fig. 2. Ungual fibroma on the right hallux. Histopathologically rich

cellular granulation tissue infiltrated by leucocytes was found.

Table 1. Laboratory Data on Admission

Urinaly sis Bl oo d ch em is tr y

P rotein (+ + ) G l u c o s e 7 4 m g / d l

B lo o d (- ) T . B i l . 0 . 8 m g / d l

G l u c o s e ( - ) G O T 1 4 I U / 1

P u s (+ ) G P T l l I U / 1

S e d i m e n t 1 0 - 1 5 W B C / H P F y - G T P 3 4 I U / 1

P r o t e i n E L F O a l b u m i n L D H 3 3 9 I U A

C P K 5 5 IU /1

P erip her al bloo d T - C h o 1 1 9 4 m g / d l

R B C T G 1 8 7 m g / d l

H t 3 7 % A L P 8 0 3 IU /1

R et 1.2 % T - P r o t 6 . 6 g / d l

W B C 5 6 0 0 / m m J A lb 5 5 %

B an d s 7 % oti-g lb 3 %

N e u tr. 5 4 % o c 2 - g l b 1 1 %

E o s. 4 % 6 - g l b 1 O %

L y . 3 0 % Y - g l b 1 6 %

M o n o . B U N 3 1 m g / d l

P l a t 1 4 . 1 x l O 4 / m m 3 C r e a t i n i n e 1 . 6 2 m g / d l

U r i c a c i d 7 . 3 m g / d l

N a 1 3 6 m E q / l

E S R 1 1 m m / h 4. 5 m Eq /1

C 1 9 1 m E q / 1

C a 1 . 5 7 m m o l / l

C a + + 0 . 7 m m o l / 1

M g 0 . 8 2 m m o l / 1

1.0 m mol /1

of the vertebral end plates (subchondral sclerosis). Tibial andfibular radiography revealed discrete, uneven thickening of thecortices in the proximal two-thirds of the tibia and fibula.

Internal Medicine Vol. 32, No. 7 (July 1993) 575

Rado et al

Table 2. Laboratory Data on Admission

E nd o c r i n e fi n d i n g s , s e r u m l ev e l s A c i d - b a s e f i n d i n g s2 5 - O H - D v i t a m i n 2 2 n m o l / l B l o o d p H 7 . 2 8

1 8 n m o l / 1 B l o o d H C O 3 1 2 . 8 m m o l / 1( n o r m . 6 0 - 2 0 0 n m o l / 1 ) U r i n e p H 6 . 1 5

P T H 1 . 1 8 n g / 1(no rm. 0. 3-0 .6 ngA )

T h y r o x i n e 6 . 4 4 j x g / d l D r u g s e r u m l e v e l sC o r t i s o 1 8 a . m . 2 1 u g / d l P r i m i d o n e 1 2 . 5 m g / 1

4 p . m . 8 . 4 ¥ i g / d ¥ ( n o r m . 3 - 1 5 m g / 1 )2 4 p . m . 5 . 8 | i g / d l P h e n y t o i n 2 . 5 m g / 1

(n or m. 10 -2 0 mg/ 1)P h e n o b a r b i t a l 1 9 . 9 m g / 1

( no r m. 2( M O m g/ 1)

R en al fu n ctio n s2 4 h r u r i n e v o l u m e 1 7 4 4 ｱ 1 5 0 m l ( N = 9 )C r e a t i n i n e c l . 4 9 ｱ 2 . 6 m l / m i n

3 1 7 ｱ 1 4 m O s m / k g(ad lib H2 O inta ke)

2 9 1 m O s m / k g

a f t e r 1 8 h ou r s H 2 O d e p r . 4 0 3 m O s m /k ga f t e r d D D A V P n o c h a n g e ( r e f . 5 )a f t er 1 8 h o u rs H 2 O d e p r. 2 9 9 m O s m / k g

pH

BloodPER OS

UrinePER OS67mmol

5 Hours

Fig. 3. Results of the bicarbonate loading tests before and after 1 -25-(OH)2-D vitaminand calcium carbonicum treatment. High urinary pH in the presence of acidotic blood pHindicated renal tubular acidosis. No difference was found between urinary and blood pCO2(not indicated here) suggesting a distal type of RTA.

Radiography of the hands and feet showed cyst-like resorptionswith sclerotic margins, uneven thickening of the lateral corticesand in some places, narrowing of the medullary canal of themetacarpals, metatarsals and phalanges (Fig. 4). Skull radiog-raphy showed multiple areas of calcification. Cranial computed

tomography showed greater and smaller calcified subependymalnodules in the cisterna magna, in the left posterior recess of thefourth ventricle, in the temporal horn of left lateral ventricle andin both lateral ventricles (Fig. 5).Renal ultrasound revealed irregular contours and shape of



Fig. 4. Radiography of the hand is characteristic of tuberous sclerosis.Uneven thickening of the lateral cortices , narrowing of the medullary canal andcyst-like resorptions can be seen.

Fig. 5. Computed tomography of the skull demonstrating severalcalcifications.

both kidneys and loss of a defined corticomedullary margin. Inthe irregular structure there were some small cysts and severalhighly reflective masses, the latter seemed to be angiomyo-lipomas. Renal computed tomography confirmed moderateenlargement of the left kidney, irregular outlines and decreasedparenchyma of both kidneys. The examination demonstrated asponge-like structure, low attenuation masses, and 2-3 cysts inthe superficial layer of the cortices. It also revealed calycealdeformity especially in the left kidney. Bone scintigraphyshowed multiple areas of markedly increased uptake in the

posterior arches of left VIII-XI and right VIII and XI ribs.Single photon absorption densitometry detected radius bonemineral content (BMC) 0.427±0.009 g/cm (SD) (Gamma NK-364 device). Dual photon absorption densitometry detectedfemoral neck bone mineral density (BMD) 0.578 g/cm2, (score-3.2), lumbar 2-4 vertebrae BMD0.693 g/cm2, (Z score- 2.9)(Norland device). In the bone biopsy specimen from the iliaccrest significant demineralization, structural desorganizationand multiple micro fractures could be seen. Few thinnedtrabeculas, large, irregular channels lined with abundantunmineralized osteoid were present. Neurologic examinationproved preserved cranial nerve functions, and the absence ofparesis or sensory loss, but it revealed proximal muscle weak-ness in the lower extremities probably due to myopathy.Funduscopic examination showedmild narrowing of the arter-ies. Electroencephalography revealed the synchronization inmoderately regular alpha type background activity. Typicalepileptiform activity could not be found. Electro-myography inthe regions of m. quadriceps femoris and m. tibialis detectednormal electric activity during maximumcontraction. Thecharacter and duration of the action potentials were normal.Maximumamplitude was4 mV.There wasno spontaneousactivity. Electroneurography (ENG): the motor conductionvelocity was 4 1 m/sec in the right peroneal nerve (distal latency:0.44, 4 msec) and 42 m/sec in the left peroneal nerve (distallatency: 0.44, 4 msec), which suggested polyneuropathy. Aftertreatment, the motor conduction velocity of both peronealnerves, and the distal latency on the right side improved, themotor conduction velocity was 48 m/sec on the right side and50 m/sec on the left side (distal latency 0.38, 3.5 msec and 0.44,4 msec respectively). The muscle biopsy showed moderatelyatrophic muscle fibres with partial replacement by fat. In someareas the normal structure could not be recognized.Treatment was initiated with 1-25-dihydroxyvitamin D(Rocaltrol, Hoffman La Roche), administered by mouth. At thebeginning the daily dose was 0.25 |Lig, later it was increased to0.5 |ag, and afterwards the therapy was supplemented with 8 gof calcium carbonicum daily (Fig. 6). After completion of threeweeks of treatment, the patient's complaints gradually de-

creased, her back pain and bone tenderness disappeared, walk-ing ability significantly improved. The serum calcium rosefrom 1.57 mmol/1 to 2.3 mmol/1, the ionized calcium increasedfrom 0.7 mmol/1 to 1.3 mmol/1. The serum alkaline phosphatasefrom 803 U/l (after the period depicted in Fig. 6) returned tonormal (320 U/l). On ECG, the long QT time was reduced tonormal (on March 6, 1991, QT was 0.40 sec beside of 61/minheart rate). Also the ENGshowed great improvement of themotor conduction velocity on the course of therapy (see above).The patient was discharged from the hospital with completeresolution of her back pain and bone tenderness. In the subse-quent year her motion ability was practically normal.

Discussion

Our patient's musculoskeletal disorder developed as a con-sequence of the combination of the following three abnormali-


Rado et al

Urine pH

Blood pHo-oSerumHCO3

(mmol/1)

SerumCalcium(mmol/1)

SerumAlkaline

Phosphatase(U/l)

-7.35

800

750

700

650600

550

500 -

l-25-(OH)2 Vitamin D

v/jv/////y///////Y/////7j^3?*m?mm^l

6.19

CaCU3 l

6.14 6.18 6.266.89 6.30

5.985.55 5.68 6.13 6.96 7.10

0 10 20 30 40 50 60 70 80100 110 120 130 140 150 160

Days,

Fig. 6. Effect of 1-25-(OH)2-D vitamin and calcium carbonicum therapy "in long section" on differenturine and blood values. The increase in serum calcium and decrease in serum alkaline phosphatase wasconspicuous.

ties: 1) tuberous sclerosis which was accompanied by epilepsy,2) anticonvulsant osteomalacia due to the long-term poly-therapy with antiepileptic compounds, 3) renal tubular acidosiswhich likely further deteriorated the metabolic abnormalities ofthe bone. Anticonvulsant osteomalacia and myopathy, verifiedby histological findings and by the sensitive photon absorptio-metry revealing extensive demineralization in the bone werefound behind the musculoskeletal disability and pain. Also,nerve conduction disorder, presumably caused by drug-in-duced D hypovitaminosis, was confirmed by electrophysio-logical studies. Onthe other hand, calcium carbonicumand 1-25 -dihydroxyvitamin D treatment resulted in the normalizationof biochemical abnormalities and significant healing ofmusculoskeletal disease.

Tuberous sclerosis is often accompaniedby specific radio-logical abnormalities in the bones; nevertheless, the motionability is usually not limited by these abnormalities. All bonesmay be involved with osteoblastic lesions; the characteristicchanges are patches of osteosclerosis. The bones in the handsand feet may show cyst-like areas, particularly in the distalphalanges (Fig. 4). The long tubular bones often show corticalthickening (1, 2).

Characteristic features of anticonvulsant osteomalacia con-sist of hypocalcemia, elevated serum alkaline phosphatase,decreased serum hydroxycholecalciferol (25-OH-D) level andlow BMC(7, 8). There are controversial opinions concerningthe serum level ofphosphorous (9-1 2). The development of thebone disorder depends on the duration of treatment, type ofanticonvulsant drugs, use of drugs alone or in combination ( 10),but other factors can play important role as well (13-16). The

basic pathophysiological mechanism behind the bone disease isthe induction of hepatic microsomalenzymesby anticonvulsantsresulting in increased metabolic inactivation of vitamin D andits metabolites (7). Anticonvulsants (mainly phenytoin) alsohave a direct inhibitory effect on the intestinal transport ofcalcium (17). Hypocalcemia is accompanied by secondary

hyperparathyroidism, and the increased level of parathyroidhormonestimulates the activity of 1 alpha-hydroxylase enzymein the kidneys (1 8). The increased enzyme activity can explainthe normal or high levels of dihydroxyvitamin D occurring inthe presence of the lower levels of 25-hydroxyvitamin D (19,20). Resistance to the action of parathyroid hormone and 1 -25-dihydroxyvitamin D on bone resorption (most important fac-tors in the defense against hypocalcemia) mayalso be caused byanticonvulsant drugs (8, 1 1). An additional deteriorating factorplaying a role in bone metabolism is the inhibitory effect ofphenytoin and primidone on basal and calcium stimulatedcalcitonin secretion (21). Since vitamin D2 and D3, two com-pounds of vitamin D act differently in anticonvulsant osteo-malacia but similarly in classical osteomalacia, concerning theBMCand serum calcium levels; apparently the metabolism ofvitamin D2 and D3 is affected differently by anticonvulsants (22,23).

Wecan summarize the mechanisms of anticonvulsant drugswhich impair calcium and bone metabolism: 1) induction ofhepatic microsomal enzymes, resulting in increased inactiva-tion of vitamin D (7), 2) inhibitory effect on intestinal calciumabsorption (17), 3) end-organ hyporesponsiveness to bothparathyroid hormone and 1 -25 -dihydroxyvitamin D in the bone(1 1, 20), 4) inhibition of calcitonin secretion in the thyroid



gland (21), 5) different metabolic fate of vitamin D2 and D3 (22,23).

Renal tubular acidosis (6) was one more factor which possi-bly further deteriorated our patient' s bone lesions (24-26). Therenal tubular acidosis was of the distal type and it could bepossibly due to the angiomyolipomatosis associated with tuber-ous sclerosis. Since in the defense against chronic metabolicacidosis the bone provides buffer reserves, acid retention canresult in calcium losses and slow dissolution of the bone mineral(24). In addition, the chronic acidosis itself can suppress thenormal production of 1-25-dihydroxyvitamin D (25), andhyperparathyroidism per se can cause a disturbance in the acid-base balance (18). Our patient's serum level of parathyroidhormone was initially increased, however, after effective vita-min D therapy the persistence of the renal tubular acidosis (Fig.3) indicated that it was not caused by hyperparathyroidism and/or hypo-D-vitaminosis but probably by the tuberous sclerosis-induced anatomic derangement of the kidneys.In summary, in our patient three disorders inducing bonelesions were present simultaneously: tuberous sclerosis,

anticonvulsant osteomalacia and renal tubular acidosis. The 1 -25-dihydroxyvitamin D and calcium carbonicum therapy re-sulted in dramatic clinical and biochemical improvement. Onthe basis of our experience, in epileptic patients also sufferingfrom renal diseases, anticonvulsant therapy may be particularlyhazardous, though the consequences - owning 1-25-

dihydroxyvitamin D- are muchless of a threat to these patientsin recent years.

Acknowledgments: This study was supported by a grant from the Hungar-ian Scientific Health Council of the Health Ministry. Weexpress our sincerethanks to Dr. Eva Pato for the cooperation in the case study, to Prof. Dr. AttilaBajtai for the histological studies, to Dr. Csaba Banos for the bone scintigraphy,to Dr. Andras Farago for the EMGexamination, to Dr. Sandor Forgacs for theradiological studies, and to Dr. Janos Sziics for performing the densitometryand vitamin D and PTHRIA assays.

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metabolic bone disease (anticonvulsant osteomalacia) and ......case report metabolic bone disease...

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